Download Amended Safety Assessment of Monoglyceryl ...

Amended Safety Assessment of Monoglyceryl Monoesters as Used in Cosmetics

Status: Re-Review for Panel Review Release Date: August 28, 2015 Panel Meeting Date: September 21-22, 2015 The 2015 Cosmetic Ingredient Review Expert Panel members are: Chairman, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D., Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is Lillian J. Gill, D.P.A. This safety assessment was prepared by Monice M. Fiume, Assistant Director/Senior Scientific Analyst/Writer and Bart Heldreth, Ph.D., Chemist.

© Cosmetic Ingredient Review 1620 L Street, NW, Suite 1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651 ♢ fax 202.331.0088 ♢

[email protected]

mailto:[email protected]

Commitment & Credibility since 1976

Memorandum To: CIR Expert Panel Members and Liaisons From: Monice M. Fiume MMF Assistant Director/Senior Scientific Analyst Date: August 28, 2015 Subject: Amended Safety Assessment of Monoglyceryl Monoesters as Used in Cosmetics Enclosed is the Re-Review of the Amended Safety Assessment of Monoglyceryl Monoesters as Used in Cosmetics. (It is identified as glyest092015rep in the pdf document.) In 1982, the Panel concluded that glyceryl stearate and glyceryl stearate SE are safe for topical application to humans. In accordance with its Procedures, CIR evaluates the conclusions of previously-issued reports every 15 years to determine whether the conclusion should be reaffirmed. There is no record of glyceryl stearate being re-reviewed, so that process is now being initiated. The Panel has issued 4 final reports on 35 similar ingredients that seem appropriate to include in this re-review; all of those ingredients are safe as used. Also, there are 8 additional cosmetic ingredients that have not yet been reviewed that have been identified as appropriate for inclusion. Table 1 provides a complete list of all 45 ingredients. All of the ingredients that are being proposed for inclusion in this report are similar because they are structurally-constituted of the esterification products of glycerin and fatty acids. A report strategy was presented to the Panel at the December 2014 meeting (see glyest092015strat_memo), proposing that a much larger group be included as part of the re-review of glyceryl stearate. However, after further consideration by the CIR staff, it was determined that two separate documents should actually be developed: 1.) the monoglyceryl monoesters report (enclosed), and 2.) a report on the polyglyceryl fatty acid esters (to be presented at the December meeting). Two other issues need to be acknowledged. First, is one of the ingredients previously-reviewed (in 2004) glyceryl arachidonate. The data were insufficient to support the safety of this ingredient, and therefore glyceryl arachidonate is not part of the current re-review because ingredients with insufficient data are not re-reviewed. Second, that same report included an ingredient identified as glyceryl stearate/maleate. Although that name was listed in the Inter-national Cosmetic Ingredient Dictionary as an ingredient, that was an error. It is actually glyceryl stearate/malate that is an ingredient, and glyceryl stearate/malate is proposed for inclusion in the re-review. Concentration of use data were received from the Council and are included in this package (glyest092015data). Also included are VCRP data (glyest092015FDA. You will note that, with the exception of glyceryl rosinate and glyceryl hydrogenated rosinate (for which concentration of use has increased), the frequency of use of these ingredients has increased, but the concentration of use generally has not. The original review of glyceryl stearate and the four safety assessments referred to above are also provided: glyest092015prev_1: Final Report on the Safety Assessment of Glyceryl Stearate and Glyceryl Stearate/SE (1982) glyest092015prev_2: Final Report on the Safety Assessment of Glyceryl Oleate (1986) glyest092015prev_3: Final Report of the ·Amended Safety Assessment of [Glyceryl Monoesters] (2004) glyest092015prev_4: Final Report on the Safety Assessment of Glyceryl Ricinoleate (1988) glyest092015prev_5: Final Report on the Safety Assessment of Ricinus Communis (Castor) Seed Oil [-derived ingredients] (2007)

Distributed for Comment Only -- Do Not Cite or Quote

The Panel is now being asked to consider whether a re-review of this ingredient group is appropriate, first considering whether new data are a reason to re-open the review. If the new data presented in the report simply reaffirm the original conclusion, then is it appropriate to re-open the review to include the proposed “add-ons”.


__________________________________________________________________________________________ 1620 L Street, NW, Suite 1200, Washington, DC 20036

(Main) 202-331-0651 (Fax) 202-331-0088

(Email) [email protected] (Website) www.cir-safety.org

Commitment & Credibility since 1976

Memorandum

To: CIR Expert Panel Members, CIR SSC Members, and Liaisons From: Bart Heldreth, PhD, Chemist Date: October 9, 2014 Subject: Request for Endorsement of a Review Strategy for Glyceryl Esters as Used in Cosmetics In 1982, the Journal of the American College of Toxicology published the Panel’s safety assessment of the cosmetic ingredients Glyceryl Stearate and Glyceryl Stearate SE (Journal of the American College of Toxicology 1(4):169-192, 1982).

O O

OH

H

n

H3C

O

Figure 1. Glyceryl Stearate, wherein n is one. At that time the Panel’s conclusion was:

On the basis of the available animal data and clinical experience presented in this report, the Panel concludes that Glyceryl Stearate and Glyceryl Stearate SE are safe for topical application to humans in the present practices of use and concentration.

And of note in the discussion:

Clinical safety data are limited, but long clinical experience and abundant animal studies prove these compounds to be nonsensitizing, nonphototoxic and nonphotosensitizing. Human phototesting, single and repeated patch testing has been carried out on too few subjects, but none of the available data provides suspicion of risk associated with the use of Glyceryl Stearate and Glyceryl Stearate SE as cosmetic ingredients. Furthermore, chemical manufacturing worker experience for 14 years has produced no adverse employee reactions.

According to CIR procedures, the time to consider this assessment for re-review has transpired. In agreement with our 2014 Re-Review Priority document, we had proposed the addition of seventy-three ingredients comprising other mono-glyceryl fatty acid mono-esters, sharing the core structure depicted in Figure 2, to this re-review.


- 2 -

Figure 2. Generic structure of mono-glyceryl fatty acid mono-esters, wherein one R group represents the residue of a certain fatty acid, the other two R groups each represent hydrogen, and n is one.

However, a related group of ingredients is also slated on the 2015 new report Priority List. This grouping was given the draft report name “Polyglyceryl-X Fatty Acid Esters.” The ingredients in this group of two hundred eighty-two share in common the core structure depicted in Figure 3 and are each Glyceryl Esters, comprising at least one, and no more than twenty, glyceryl repeat unit(s) and at least one fatty acid ester.

Figure 3. Generic structure, wherein R represents hydrogen or the residue of certain fatty acids, and n varies from 1 to 20.

Since the ingredients in our originally proposed re-review of Glyceryl Stearate share the same structural core as those ingredients of our new report, we herein propose the assemblage of these two groupings into one report, Glyceryl Esters. The ingredients in this combined report, the Glyceryl Esters, are each structurally constituted of the esterification products of glycerin and fatty acids. Therein, the ingredient grouping would be broken down into sub-groups, delineated by structural characteristics such as the value of “n” or how many “R” groups are representative of fatty acid residues. Accordingly, if some rationale to separate these ingredients along those structural lines becomes apparent, once the culmination of toxicological data is available and summarized, such lysing into two or more concurrent reports will be rather straight-forward. A rough draft of the sub-groupings is included herein, as Table 1.

In consideration of the size of this proposed report, please remember the success of the even larger CIR safety assessment titled Alkyl PEG Ethers, the 369 ingredients of which also varied by the number of polyether (polyethylene glycol instead of polyglycerol) repeat units and the number of attached fatty alkyl chains.

Accordingly, the question being asked is, should an SLR be prepared comprising all 331 of the ingredients listed in Table 1?


- 3 -

Table 1. Definitions, idealized structures, and functions of the ingredients in this safety assessment. (INCI Dictionary; CIR Staff)

Ingredient CAS No. Definition & Structure

Monoglyceryl Monoesters (a.k.a Monoglycerides)

Glyceryl Acetate

26446-35-5

Glyceryl Acetate is the ester of Acetic Acid and Glycerin.

Glyceryl Adipate

26699-71-8

Glyceryl Adipate is the ester of glycerin and adipic acid that conforms to the

formula.

Glyceryl Alginate Glyceryl Alginate is the ester of glycerin and Alginic Acid. (Alginic Acid is the carbohydrate obtained by the alkaline extraction of various species of brown seaweed, Phaeophyceae.)

wherein RC(O)- represents the residue of Alginic Acid

Glyceryl Arachidate

30208-87-8

50906-68-8

Glyceryl Arachidate is the monoester of glycerin and Arachidic Acid. It

conforms generally to the formula

Glyceryl Arachidonate

129691-05-0

35474-99-8

Glyceryl Arachidonate is the monoester of glycerin and arachidonic acid. It

conforms the formula

Glyceryl Behenate

6916-74-1

77538-19-3

30233-64-8

Glyceryl Behenate is the monoester of glycerin and behenic acid. It


Glyceryl Behenate/Eicosadioate Glyceryl Behenate/Eicosadioate is a mixture of esters of Glycerin with behenic and eicosandioic acids.

wherein RC(O)- represents the residue of Behenic or Eicosadioic Acid

Glyceryl Caprate

11139-88-1

26402-22-2

Glyceryl Caprate is the monoester of glycerin and capric acid. It conforms to

the formula

Glyceryl Caprylate

26402-26-6

Glyceryl Caprylate is the monoester of glycerin and caprylic acid. It

conforms to the formula


- 4 -



Glyceryl Caprylate/Caprate Glyceryl Caprylate/Caprate is a monoester of glycerin esterified with a mixture of caprylic and capric acids.

wherein RC(O)- represents the residue of Caprylic or Capric Acid

Glyceryl

Citrate/Lactate/Linoleate/Oleate

Glyceryl Citrate/Lactate/Linoleate/Oleate is glycerin esterified with a blend of citric, lactic, linoleic and oleic acids.

wherein RC(O)- represents the residue of citric, lactic, linoleic, or oleic acid

Glyceryl Cocoate

61789-05-7

Glyceryl Cocoate is the monoester of glycerin and coconut fatty acids. It conforms generally to the formula:

where RC(O)- represents the fatty acids derived from coconut oil

Glyceryl Cocoate/Citrate/Lactate Glyceryl Cocoate/Citrate/Lactate is glycerin esterified with a blend of coconut, citric and lactic acids.

wherein RC(O)- represents the residue of coconut, citric, or lactic acid

Glyceryl Erucate

28063-42-5

Glyceryl Erucate is the monoester of glycerin and erucic acid. It conforms

generally to the formula

Glyceryl Ethylhexanoate Glyceryl Ethylhexanoate is the ester of glycerin and ethylhexanoic acid that


Glyceryl Ethylhexanoate/Stearate/

Adipate

Glyceryl Ethylhexanoate/Stearate/Adipate is Glycerin esterified with a blend of 2-ethylhexanoic acid, Stearic Acid and Adipic Acid.

wherein RC(O)- represents the residue of 2-ethylhexanoic, stearic, or adipic acid

Glyceryl Heptanoate

26402-24-4

Glyceryl Heptanoate is the glyceryl ester of heptanoic acid that conforms to

the formula


- 5 -



Glyceryl Hydrogenated

Rapeseedate

Glyceryl Hydrogenated Rapeseedate is the monoester of glycerin and the fatty acids derived from Hydrogenated Rapeseed Oil.

wherein RC(O)- represents the residue of the fatty acids derived from Hydrogenated Rapeseed Oil

Glyceryl Hydrogenated Rosinate Glyceryl Hydrogenated Rosinate is the monester of glycerin and hydrogenated mixed long chain acids derived from rosin.

wherein RC(O)- represents the residue of the hydrogenated mixed long chain acids derived from rosin

Glyceryl Hydrogenated Soyate Glyceryl Hydrogenated Soyate is the monoester of Glycerin and hydrogenated mixed long chain acids derived from soy.

wherein RC(O)- represents the residue of the hydrogenated mixed long chain acids derived from soy

Glyceryl Hydroxystearate

1323-42-8

Glyceryl Hydroxystearate is the monoester of glycerin and Hydroxystearic

Acid. It conforms generally to the formula

Glyceryl Hydroxystearate/Oleate

Esters

Glyceryl Hydroxystearate/Oleate Esters is a mixture of esters formed by the reaction of Glycerin with a blend of Hydroxystearic Acid and Oleic Acid.

wherein RC(O)- represents the residue of hydroxystearic or oleic acid

Glyceryl Isopalmitate Glyceryl Isopalmitate is the monoester of glycerin and a branched chain 16

carbon aliphatic acid. It conforms to the formula

Glyceryl Isostearate

61332-02-3

66085-00-5

Glyceryl Isostearate is the monoester of glycerin and Isostearic Acid. It


Glyceryl Isostearate/Myristate Glyceryl Isostearate/Myristate is the monoester of glycerin esterified with a blend of isostearic and myristic acids.

wherein RC(O)- represents the residue of isostearic or myristic acid


- 6 -



Glyceryl

Isotridecanoate/Stearate/Adipate

Glyceryl Isotridecanoate/Stearate/Adipate is Glycerin esterified with a blend of isotridecanoic acid, Stearic Acid and Adipic Acid.

wherein RC(O)- represents the residue of isotridecanoic, stearic, or adipic acid

Glyceryl Lanolate Glyceryl Lanolate is the monoester of glycerin and Lanolin Acid.

wherein RC(O)- represents the residue of lanolin acid

Glyceryl Laurate

142-18-7

27215-38-9

37318-95-9

Glyceryl Laurate is the monoester of glycerin and lauric acid. It conforms


Glyceryl Laurate SE Glyceryl Laurate SE is a self-emulsifying grade of Glyceryl Laurate that contains some sodium and/or potassium laurate.

Glyceryl Laurate/Oleate Glyceryl Laurate/Oleate is the monoester of glycerin esterified with a blend of lauric and oleic acids.

wherein RC(O)- represents the residue of lauric or oleic acid

Glyceryl Linoleate

2277-28-3

26545-74-4

37348-65-5

Glyceryl Linoleate is the monoester of glycerin and linoleic acid. It


Glyceryl Linolenate

18465-99-1

56554-41-7

Glyceryl Linolenate is the monoester of glycerin and linolenic acid. It


Glyceryl Montanate

68476-38-0

71035-02-4

Glyceryl Montanate is the monoester of glycerin and Montan Acid Wax.

wherein RC(O)- represents the residue of montan acid wax


- 7 -



Glyceryl Myristate

27214-38-6

589-68-4

Glyceryl Myristate is the monoester of glycerin and myristic acid. It


Glyceryl Oleate

111-03-5

161403-66-3

25496-72-4

37220-82-9

68424-61-3

Glyceryl Oleate is the monoester of glycerin and oleic acid. It conforms


Glyceryl Oleate SE Glyceryl Oleate SE is a self-emulsifying grade of Glyceryl Oleate that contains some sodium and/or potassium oleate.

Glyceryl Oleate/Elaidate Glyceryl Oleate/Elaidate is a mixture of monoglycerides of oleic and elaidic acids.

wherein RC(O)- represents the residue of elaidic or oleic acid

Glyceryl Olivate Glyceryl Olivate is the monoester of glycerin and the fatty acids derived from olive oil. It conforms generally to the formula

wherein RC(O)- represents the fatty acids derived from olive oil

Glyceryl Palmitate

26657-96-5

542-44-9

Glyceryl Palmitate is the monoester of glycerin and palmitic acid. It


Glyceryl Palmitate/Stearate

68002-71-1

Glyceryl Palmitate/Stearate is the monoester of glycerin esterified with a blend of palmitic and stearic acids.

wherein RC(O)- represents the residue of palmitic or stearic acid

Glyceryl Palmitoleate Glyceryl Palmitoleate is the monoester of glycerin and palmitoleic acid. It


Glyceryl Pentadecanoate

122636-37-7

Glyceryl Pentadecanoate is the monoester of glycerin and pentadecanoic acid. It conforms generally to the formula


- 8 -



Glyceryl Ricinoleate

1323-38-2

141-08-2

5086-52-2

Glyceryl Ricinoleate is the monoester of glycerin and ricinoleic acid. It


Glyceryl Ricinoleate SE Glyceryl Ricinoleate SE is a self-emulsifying grade of Glyceryl Ricinoleate containing sodium and/or potassium stearate.

Glyceryl Rosinate

8050-31-5

Glyceryl Rosinate is the monoester of glycerin and mixed long chain acids derived from Rosin.

wherein RC(O)- represents the residue of mixed long chain acids derived from Rosin

Glyceryl Stearate

11099-07-3

123-94-4

31566-31-1

85666-92-8

Glyceryl Stearate is the monoester of glycerin and stearic acid. It conforms


Glyceryl Stearate SE

11099-07-3

85666-92-8

Glyceryl Stearate SE is a self-emulsifying grade of Glyceryl Stearate that contains some sodium and/or potassium stearate.

Glyceryl Stearate/Malate Glyceryl Stearate/Malate is the ester of glycerin esterified with a blend of stearic and malic acids.

wherein RC(O)- represents the residue of stearic or malic acid

Glyceryl Tallowate Glyceryl Tallowate is the monoester of glycerin and tallow fatty acids. It conforms generally to the formula

wherein RC(O)- represents the residue of the fatty acids derived from tallow

Glyceryl Undecylenate

123759-97-7

62285-15-8

Glyceryl Undecylenate is the ester of glycerin and undecylenic acid that



- 9 -



Monoglyceryl Diesters (a.k.a. Diglycerides) and Monoglyceryl Sesquiesters (a.k.a. mixtures of Mono- and Diglycerides)

Glyceryl Sesquioleate Glyceryl Sesquioleate is a mixture of mono- and diesters of glycerin and oleic acid.

wherein R- represents hydrogen or the residue of oleic acid

Glyceryl

Sesquioleate

Glyceryl Palmitate Lactate

Glyceryl Palmitate Lactate is the lactic acid ester of glyceryl palmitate. It


Glyceryl

Palmitate Lactate

Glyceryl Stearate/Acetate Glyceryl Stearate/Acetate is the diester of glycerin esterified with a blend of stearic and acetic acids.

wherein RC(O)- represents the residue of acetic or stearic acid

Glyceryl Stearate Citrate

39175-72-9

55840-13-6

Glyceryl Stearate Citrate is the citric acid ester of Glyceryl Stearate. It


Glyceryl Stearate Lactate Glyceryl Stearate Lactate is the lactic acid ester of Glyceryl Stearate. It


Glyceryl Stearate Succinate Glyceryl Stearate Succinate is the succinic acid ester of Glyceryl Stearate.

Monoglyceryl Triesters (a.k.a. Triglycerides) & mixtures of Monoglyceryl Mono-, Di-, & Triesters (a.k.a. Mono-, Di, & Triglycerides)

Glyceryl Isostearates Glyceryl Isostearates is a mixture of the mono-, di- and triesters of glycerin and isostearic acid.

O

O

OR

RO

CH3

CH3

wherein R represents hydrogen or the residue of isostearic acid (one example of an “iso”)

Glyceryl

Isostearates

Glyceryl Laurate Diacetate

30899-62-8

Glyceryl Laurate Diacetate is the organic compound that conforms generally

to the formula


- 10 -



Glyceryl Stearate Diacetate

84931-78-2

Glyceryl Stearate Diacetate is the organic compound that conforms to the

formula

Glyceryl Stearates Glyceryl Stearates is a mixture of the mono-, di- and triesters of glycerin and stearic acid.

O

O

OR

RO CH3

wherein R represents hydrogen or the residue of stearic acid

Glyceryl Tribehenate/Isostearate/

Eicosandioate

Glyceryl Tribehenate/Isostearate/Eicosandioate is the triester of glycerin with a mixture of Behenic Acid, Isostearic Acid, and eicosandioic acid.

wherein R represents the residue of behenic, isostearic, or eicosandioic acid

Glyceryl Tripalmate/Palm

Kernelate/Olivate/Macadamiate/

Rapeseedate

Glyceryl Tripalmate/Palm Kernelate/Olivate/Macadamiate/Rapeseedate is the triester of glycerin with a mixture of fatty acids derived from palm oil, palm kernel oil, olive oil, macadamia nut oil and rapseed oil.

wherein R represents the residue of the fatty acids derived from palm oil, palm kernel oil, olive oil, macadamia nut oil and rapseed oil

Polyglyceryl Monoesters

Acacia Decurrens/Jojoba/

Sunflower Seed Wax

Polyglyceryl-3 Esters

Acacia Decurrens/Jojoba/Sunflower Seed Wax Polyglyceryl-3 Esters is a product obtained by the transesterification of Polyglycerin-3 with a mixture of Acacia Decurrens Flower Wax, Simmondsia Chinensis (Jojoba) Seed Wax and Helianthus Annuus (Sunflower) Seed Wax.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification of the respective tryglyceride waxes) from Acacia Decurrens Flower Wax, Simmondsia Chinensis (Jojoba) Seed Wax and Helianthus Annuus (Sunflower) Seed Wax, and n is 3

Adansonia Digitata Seed Oil


Adansonia Digitata Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Adansonia Digitata Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Adansonia Digitata Seed Oil, and n is 6


- 11 -



Almond Oil/Polyglyceryl-10 Esters Almond Oil/Polyglyceryl-10 Esters is the product obtained by the transesterification of Prunus Amygdalus Dulcis (Sweet Almond) Oil and Polyglycerin-10.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Prunus Amygdalus Dulcis (Sweet Almond) Oil, and n is 10

Apricot Kernel Oil Polyglyceryl-3

Esters

Apricot Kernel Oil Polyglyceryl-3 Esters is the product obtained by the transesterification of Prunus Armeniaca (Apricot) Kernel Oil and Polyglycerin-3.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Prunus Armeniaca (Apricot) Kernel Oil, and n is 3


Esters




Esters




Esters




- 12 -




Esters



Argan Oil Polyglyceryl-6 Esters Argan Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Argania Spinosa Kernel Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Argania Spinosa Kernel Oil, and n is 6

Astrocaryum Vulgare Oil


Astrocaryum Vulgare Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Astrocaryum Vulgare Kernel Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Astrocaryum Vulgare Kernel Oil, and n is 6

Avocado Oil Polyglyceryl-6 Esters Avocado Oil Polyglyceryl-6 Esters is the product obtained by the transesterificaton of Persea Gratissima (Avocado) Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Persea Gratissima (Avocado) Oil, and n is 6

Babassu Oil Polyglyceryl-4 Esters Babassu Oil Polyglyceryl-4 Esters is the product of the transesterification of Orbignya Oleifera Seed Oil and Polyglycerin-4.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Orbignya Oleifera Seed Oil, and n is 4

Babassu Oil Polyglyceryl-6 Esters Babassu Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Orbignya Oleifera Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Orbignya Oleifera Seed Oil, and n is 6


- 13 -



Bertholletia Excelsa Seed Oil


Bertholletia Excelsa Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Bertholletia Excelsa Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Bertholletia Excelsa Seed Oil, and n is 6

Borage Seed Oil Polyglyceryl-4

Esters

Borage Seed Oil Polyglyceryl-4 Esters is the product obtained by the transesterification of Borago Officinalis Seed Oil and Polyglycerin-4.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Borago Officinalis Seed Oil, and n is 4

Borage Seed Oil Polyglyceryl-6

Esters

Borage Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Borago Officinalis Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Borago Officinalis Seed Oil, and n is 6

Candelilla/Jojoba/Rice Bran


Candelilla/Jojoba/Rice Bran Polyglyceryl-3 Esters is a product obtained by the transesterification of Polyglycerin-3 and Euphorbia Cerifera (Candelilla) Wax, and Simmondsia Chinensis (Jojoba) Seed Wax and Oryza Sativa (Rice) Bran Wax.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Euphorbia Cerifera (Candelilla) Wax, and Simmondsia Chinensis (Jojoba) Seed Wax and Oryza Sativa (Rice) Bran Wax, and n is 3

Carapa Guaianensis Oil


Carapa Guaianensis Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Carapa Guaianensis Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Carapa Guaianensis Seed Oil, and n is 6


- 14 -



Castor Oil Polyglyceryl-6 Esters Castor Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Ricinus Communis (Castor) Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Ricinus Communis (Castor) Seed Oil, and n is 6

Cocoa Butter Polyglyceryl-6 Esters Cocoa Butter Polyglyceryl-6 Esters is the product obtained by the transesterification of Theobroma Cacao (Cocoa) Seed Butter and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Theobroma Cacao (Cocoa) Seed Butter, and n is 6

Coconut Oil Polyglyceryl-6 Esters Coconut Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Cocos Nucifera (Coconut) Oil with Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Cocos Nucifera (Coconut) Oil, and n is 6

Coffee Seed Oil Polyglyceryl-6

Esters

Coffee Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Polyglycerin-6 and Coffea Arabica (Coffee) Seed Oil.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Coffea Arabica (Coffee) Seed Oil, and n is 6

Glyceryl/Polyglyceryl-6

Isostearate/Behenate Esters

Glyceryl/Polyglyceryl-6 Isostearate/Behenate Esters is the mixture of esters formed by the reaction of Glycerin and Polyglycerin-6 with Isostearic Acid and Behenic Acid.

wherein RC(O)- represents the residue of isostearic or behenic acid, and n is 1 or 6

Hazelnut Seed Oil Polyglyceryl-6

Esters

Hazelnut Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Corylus Avellana (Hazelnut) Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Corylus Avellana (Hazelnut) Seed Oil, and n is 6


- 15 -



Linseed Oil Polyglyceryl-4 Esters Linseed Oil Polyglyceryl-4 Esters is the product obtained by the transesterification of Linum Usitatissimum (Linseed) Seed Oil and Polyglycerin-4.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Linum Usitatissimum (Linseed) Seed Oil, and n is 4

Macadamia Seed Oil


Macadamia Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Macadamia Ternifolia Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Macadamia Ternifolia Seed Oil, and n is 6

Mauritia Flexuosa Seed Oil


Mauritia Flexuosa Seed Oil Polyglyceryl-6 Esters is the product obtained by the tranesterification of the oil obtained from the seeds of Mauritia flexuosa and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from the seeds of Mauritia flexuosa, and n is 6

Olive Oil Polyglyceryl-3 Esters Olive Oil Polyglyceryl-3 Esters is the product obtained by the transesterification of Polyglycerin-3 and Olea Europaea (Olive) Fruit Oil.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Olea Europaea (Olive) Fruit Oil, and n is 3

Olive Oil Polyglyceryl-4 Esters Olive Oil Polyglyceryl-4 Esters is the product obtained by the transesterification of Olea Europaea (Olive) Fruit Oil and Polyglycerin-4.


Olive Oil Polyglyceryl-6 Esters Olive Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Olea Europaea (Olive) Fruit Oil and Polyglycerin-6.



- 16 -



Palm Kernel Oil Polyglyceryl-4

Esters

Palm Kernel Oil Polyglyceryl-4 Esters is the product obtained by the transesterification of Elaeis Guineensis (Palm) Kernel Oil and Polyglycerin-4.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Elaeis Guineensis (Palm) Kernel Oil, and n is 4

Palm Oil Polyglyceryl-3 Esters Palm Oil Polyglyceryl-3 Esters is the product obtained by the transesterification of Polyglycerin-3 and Elaeis Guineensis (Palm) Oil.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Elaeis Guineensis (Palm) Oil, and n is 3



Palm Oil Polyglyceryl-5 Esters Palm Oil Polyglyceryl-5 Esters is the product obtained by the transesterification of a glycerin polymer containing 5 units of glycerin and Elaeis Guineensis (Palm) Oil.




Parinari Curatellifolia Oil


Parinari Curatellifolia Oil Polyglyceryl-6 Esters is the product of the transesterificaiton of the oil obtained from the seeds of Parinari curatellifolia and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from the seeds of Parinari curatellifolia, and n is 6


- 17 -



Pinus Sibirica Seed Oil


Pinus Sibirica Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Pinus Sibirica Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Pinus Sibirica Seed Oil, and n is 6

Polyglyceryl-6 Adansonia Digitata

Seedate

Polyglyceryl-6 Adansonia Digitata Seedate is the ester of the fatty acids obtained from Adansonia Digitata Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Adansonia Digitata Seed Oil, and n is 6

Polyglyceryl-4 Almondate/Shea

Butterate

Polyglyceryl-4 Almondate/Shea Butterate is an ester of a mixture of fatty acids derived from almond oil and Butyrospermum Parkii (Shea) Butter with Polyglycerin-4.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Butyrospermum Parkii (Shea) Butter, and n is 4

Polyglyceryl-6 Apricot Kernelate Polyglyceryl-6 Apricot Kernelate is the ester of the fatty acids derived from Prunus Armeniaca (Apricot) Kernel Oil and Polyglycerin-6.


Polyglyceryl-10 Apricot Kernelate Polyglyceryl-10 Apricot Kernelate is the ester of the fatty acids derived from Prunus Armeniaca (Apricot) Kernel Oil and Polyglycerin-10.


Polyglyceryl-6 Argan Kernelate Polyglyceryl-6 Argan Kernelate is the ester of Polyglycerin-6 and the fatty acids obtained from Argania Spinosa Kernel Oil.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Argania Spinosa Kernel Oil, and n is 6


- 18 -



Polyglyceryl-3 Beeswax

136097-93-3

Polyglyceryl-3 Beeswax is an ester of beeswax fatty acids and Polyglycerin-3.

wherein RC(O)- represents the residue of beeswax fatty acids, and n is 3

Polyglyceryl-3 Behenate Polyglyceryl-3 Behenate is the ester of behenic acid and Polyglycerin-3.

wherein n is 3

Polyglyceryl-6 Behenate Polyglyceryl-6 Behenate is the monoester of Behenic Acid and Polyglycerin-6.

wherein n is 6

Polyglyceryl-10

Behenate/Eicosadioate

Polyglyceryl-10 Behenate/Eicosadioate is the monoester of Polyglycerin-10 and a blend of behenic and eicosadioic acids.

wherein RC(O)- represents the residue of behenic or eicosadioic acid, and n is 10

Polyglyceryl-8 C12-20 Acid Ester Polyglyceryl-8 C12-20 Acid Ester is the ester of a glycerin polymer containing 8 units of glycerin and a synthetic mixture of saturated acids containing 12 to 20 carbons in the alkyl chain.

wherein RC(O)- represents the residue of a fatty acid containing 12 to 20 carbons in the alkyl chain, and n is 8

Polyglyceryl-2 Caprate

156153-06-9

Polyglyceryl-2 Caprate is the ester of capric acid and Diglycerin.

wherein n is 2


133654-02-1

51033-30-8

74504-65-7

Polyglyceryl-3 Caprate is an ester of capric acid and Polyglycerin-3.

wherein n is 3


- 19 -




160391-93-5

74504-65-7

Polyglyceryl-4 Caprate is the ester of Capric Acid and Polyglycerin-4.

wherein n is 4

Polyglyceryl-5 Caprate Polyglyceryl-5 Caprate is the monoester of capric acid and Polyglycerin-5.

wherein n is 5

Polyglyceryl-6 Caprate Polyglyceryl-6 Caprate is the monoester of Capric Acid and Polyglycerin-6.

wherein n is 6

Polyglyceryl-10 Caprate Polyglyceryl-10 Caprate is the ester of capric acid and Polyglycerin-10.

wherein n is 10

Polyglyceryl-2 Caprylate Polyglyceryl-2 Caprylate is the ester of Caprylic Acid and Diglycerin.

wherein n is 2

Polyglyceryl-3 Caprylate

108777-93-1

Polyglyceryl-3 Caprylate is the ester of caprylic acid and Polyglycerin-3.

wherein n is 3

Polyglyceryl-4 Caprylate Polyglyceryl-4 Caprylate is the monoester of Caprylic Acid and Polyglycerin-4

wherein n is 4


- 20 -



Polyglyceryl-6 Caprylate Polyglyceryl-6 Caprylate is the monoester of caprylic acid and Polyglycerin-6

wherein n is 6

Polyglyceryl-10 Caprylate

51033-41-1

Polyglyceryl-10 Caprylate is the monoester of caprylic acid and Polyglycerin-10.

wherein n is 10

Polyglyceryl-4 Caprylate/Caprate Polyglyceryl-4 Caprylate/Caprate is the monoester of Polyglycerin-4 and a mixture of caprylic and capric acids.

wherein RC(O)- represents the residue of capric or caprylic acid, and n is 4

Polyglyceryl-6 Caprylate/Caprate Polyglyceryl-6 Caprylate/Caprate is the monoester of Polyglycerin-6 and a mixture of caprylic and capric acids


Polyglyceryl-10 Caprylate/Caprate Polyglyceryl-10 Caprylate/Caprate is the monoester of Polyglycerin-10 and a blend of caprylic and capric acids.


Polyglyceryl-6 Citrullus Lanatus

Seedate

Polyglyceryl-6 Citrullus Lanatus Seedate is the ester of the fatty acids derived from Citrullus Lanatus (Watermelon) Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Citrullus Lanatus (Watermelon) Seed Oil, and n is 6


- 21 -



Polyglyceryl-3 Cocoate Polyglyceryl-3 Cocoate is the ester of Coconut Acid and Polyglycerin-3.

wherein RC(O)- represents the residue of Coconut Acid, and n is 3

Polyglyceryl-4 Cocoate Polyglyceryl-4 Cocoate is an ester of Coconut Acid and Polyglycerin-4.


Polyglyceryl-10 Cocoate Polyglyceryl-10 Cocoate is the ester of Coconut Acid and Polyglycerin-10.


Polyglyceryl-2

Isopalmitate/Sebacate

Polyglyceryl-2 Isopalmitate/Sebacate is the mixed ester of isopalmitic acid, Sebacic Acid and Diglycerin.

wherein RC(O)- represents the residue of isopalmitic or sebacic acid, and n is 2

Polyglyceryl-2 Isostearate

73296-86-3

81752-33-2

Polyglyceryl-2 Isostearate is the ester of isostearic acid and Diglycerin.

wherein RC(O)- represents the residue of isostearic acid, and n is 2


127512-63-4

Polyglyceryl-3 Isostearate is the ester of isostearic acid and Polyglycerin-3.



63705-03-3

91824-88-3

Polyglyceryl-4 Isostearate is an ester of Isostearic Acid and Polyglycerin-4.



- 22 -



Polyglyceryl-5 Isostearate Polyglyceryl-5 Isostearate is the ester of isostearic acid and a glycerin polymer containing an average of 5 glycerin units.



126928-07-2




133738-23-5



Polyglyceryl-10 Eicosanedioate/

Tetradecanedioate

Polyglyceryl-10 Eicosanedioate/Tetradecanedioate is the ester of Polyglycerin-10 with a mixture of eicosanedioic and tetradecanedioic acids.

wherein RC(O)- represents the residue of eicosanedioic or tetradecanedioic acid, and n is 10

Polyglyceryl-4 Hazelnutseedate Polyglyceryl-4 Hazelnutseedate is an ester of the fatty acids derived from Corylus Avellana (Hazelnut) Seed Oil with Polyglycerin-4.

wherein RC(O)- represents the residue of the fatty acids derived from Corylus Avellana (Hazelnut) Seed Oil, and n is 4

Polyglyceryl-2 Isopalmitate Polyglyceryl-2 Isopalmitate is an ester of isopalmitic acid and Diglycerin.

wherein RC(O)- represents the residue of isopalmitic acid, and n is 2


- 23 -



Polyglyceryl-4 Isostearate/Laurate Polyglyceryl-4 Isostearate/Laurate is the ester of a mixture of isostearic and lauric acids with Polyglycerin-4.

wherein RC(O)- represents the residue of isostearic or lauric acid, and n is 4

Polyglyceryl-2 Laurate

96499-68-2

Polyglyceryl-2 Laurate is the ester of lauric acid and Diglycerin.

wherein RC(O)- represents the residue of lauric acid, and n is 2


51033-31-9

Polyglyceryl-3 Laurate is the ester of lauric acid and Polyglycerin-3.



74504-64-6

75798-42-4




128738-83-0

Polyglyceryl-5 Laurate is the ester of lauric acid and a glycerin polymer containing an average of 5 glycerin units.



51033-38-6




34406-66-1

Polyglyceryl-10 Laurate is an ester of lauric acid and Polyglycerin-10.



- 24 -



Polyglyceryl-10 Linoleate Polyglyceryl-10 Linoleate is the monoester of linoleic acid and Polyglycerin-10.

wherein RC(O)- represents the residue of linoleic acid, and n is 10

Polyglyceryl-2 Myristate Polyglyceryl-2 Myristate is the monoester of myristic acid and Diglycerol.

wherein RC(O)- represents the residue of myristic acid, and n is 2

Polyglyceryl-3 Myristate Polyglyceryl-3 Myristate is the ester of myristic acid and Polyglycerin-3.


Polyglyceryl-5 Myristate Polyglyceryl-5 Myristate is the monoester of myristic acid and a glycerin polymer containing 5 units of glycerin.


Polyglyceryl-6 Myristate Polyglyceryl-6 Myristate is the monoester of myristic acid and Polyglycerin-6.


Polyglyceryl-10 Myristate

87390-32-7

Polyglyceryl-10 Myristate is an ester of myristic acid and Polyglycerin-10.


Polyglyceryl-2 Oleate

49553-76-6

9007-48-1 (generic)

Polyglyceryl-2 Oleate is an ester of oleic acid and Diglycerin.

wherein RC(O)- represents the residue of oleic acid, and n is 2


- 25 -




33940-98-6

9007-48-1 (generic)

Polyglyceryl-3 Oleate is an ester of oleic acid and Polyglycerin-3.



71012-10-7

9007-48-1 (generic)




86529-98-8

9007-48-1 (generic)

Polyglyceryl-5 Oleate is the ester of oleic acid and a glycerin polymer containing an average of 5 glycerin units.



79665-92-2

9007-48-1 (generic)

Polyglyceryl-6 Oleate is the ester of oleic acid and Polyglycerin-6.



75719-56-1

9007-48-1 (generic)

Polyglyceryl-8 Oleate is an ester of oleic acid and a glycerin polymer containing an average of 8 glycerin units.



79665-93-3

9007-48-1 (generic)



Polyglyceryl-10 Palmate Polyglyceryl-10 Palmate is the ester of Palm Acid and Polyglycerin-10.

wherein RC(O)- represents the residue of palm acid, and n is 10


- 26 -



Polyglyceryl-2 Palmitate Polyglyceryl-2 Palmitate is the monoester of palmitic acid and Diglycerol.

wherein RC(O)- represents the residue of palmitic acid, and n is 2

Polyglyceryl-3 Palmitate Polyglyceryl-3 Palmitate is an ester of Palmitic Acid and Polyglycerin-3.


Polyglyceryl-6 Palmitate Polyglyceryl-6 Palmitate is the ester of Palmitic Acid and Polyglycerin-6.


Polyglyceryl-10 Palmitate Polyglyceryl-10 Palmitate is the ester of palmitic acid and Polyglycerin-10.


Polyglyceryl-6 Palmitate/Succinate Polyglyceryl-6 Palmitate/Succinate is the monoester of Polyglycerin-6 and a mixture of palmitic and succinic acids.

wherein RC(O)- represents the residue of palmitic or succinic acid, and n is 6

Polyglyceryl-4 Punicate Polyglyceryl-4 Punicate is the ester of Polyglycerin-4 and punicic acid.

wherein RC(O)- represents the residue of punicic acid, and n is 4

Polyglyceryl-3 Rice Branate Polyglyceryl-3 Rice Branate is the monoester of Polyglycerin-3 and Rice Bran Acid.

wherein RC(O)- represents the residue of rice bran acid, and n is 3


- 27 -



Polyglyceryl-3 Ricinoleate

29894-35-7 (generic)

Polyglyceryl-3 Ricinoleate is an ester of ricinoleic acid and Polyglycerin-3.

wherein RC(O)- represents the residue of ricinoleic acid, and n is 3

Polyglyceryl-5 Ricinoleate Polyglyceryl-5 Ricinoleate is the product obtained by the reaction of Ricinoleic Acid with a glycerin polymer containing 5 glycerin units.


Polyglyceryl-6 Ricinoleate Polyglyceryl-6 Ricinoleate is the ester of Polyglycerin-6 and Ricinoleic Acid.


Polyglyceryl-6 Schinziophyton

Rautanenii Kernelate

Polyglyceryl-6 Schinziophyton Rautanenii Kernelate is the ester of Polyglycerin-6 and the fatty acids obtained from Schinziophyton Rautanenii Kernel Oil.

wherein RC(O)- represents the residue of the fatty acids obtained from Schinziophyton Rautanenii Kernel Oil, and n is 6

Polyglyceryl-6 Sclerocarya Birrea

Seedate

Polyglyceryl-6 Sclerocarya Birrea Seedate is the ester of Polyglycerin-6 and the fatty acids obtained from Schinziophyton Rautanenii Kernel Sclerocarya Birrea Seed Oil.

wherein RC(O)- represents the residue of the fatty acids obtained from Sclerocarya Birrea Seed Oil, and n is 6

Polyglyceryl-3 Soyate/Shea

Butterate

Polyglyceryl-3 Soyate/Shea Butterate is an ester of a mixture of fatty acids derived from Glycine Soja (Soybean) Oil and Butyrospermum Parkii (Shea) Butter with Polyglycerin-3.

wherein RC(O)- represents the residue of the fatty acids obtained from Glycine Soja (Soybean) Oil and Butyrospermum Parkii (Shea) Butter, and n is 3


- 28 -



Polyglyceryl-2 Stearate

12694-22-3

9009-32-9 (generic)

Polyglyceryl-2 Stearate is the ester of stearic acid and Diglycerin.

wherein RC(O)- represents the residue of stearic acid, and n is 2


26855-43-6

27321-72-8

37349-34-1 (generic)

Polyglyceryl-3 Stearate is an ester of stearic acid and Polyglycerin-3.



26855-44-7

37349-34-1 (generic)

68004-11-5




37349-34-1 (generic)

Polyglyceryl-5 Stearate is the monoester of stearic acid and a glycerin polymer containing 5 units of glycerin.



95461-65-7

Polyglyceryl-6 Stearate is the ester of Stearic Acid and Polyglycerin-6.



37349-34-1 (generic)

75719-57-2

Polyglyceryl-8 Stearate is an ester of stearic acid and a glycerin polymer containing an average of 8 glycerin units.



79777-30-3

9009-32-9 (generic)




- 29 -



Polyglyceryl-3 Stearate SE Polyglyceryl-3 Stearate SE is a self-emulsifying grade of Polyglyceryl-3 Stearate that contains some sodium and/or potassium stearate.

Polyglyceryl-4 Sweet Almondate Polyglyceryl-4 Sweet Almondate is an ester of the fatty acids derived from sweet almond oil and Polyglycerin-4.

wherein RC(O)- represents the residue of the fatty acids obtained from sweet almond oil, and n is 4

Polyglyceryl-6 Trichilia Emetica

Seedate

Polyglyceryl-6 Trichilia Emetica Seedate is the ester of Polyglycerin-6 and the fatty acids obtained from Trichilia Emetica Seed Butter.

wherein RC(O)- represents the residue of the fatty acids obtained from Trichilia Emetica Seed Butter, and n is 6

Polyglyceryl-6 Undecylenate Polyglyceryl-6 Undecylenate is the an ester of Undecylenic Acid and Polyglycerin-6.

wherein RC(O)- represents the residue of undecylenic acid, and n is 6

Polyglyceryl-10 Undecylenate Polyglyceryl-10 Undecylenate is an ester of Undecylenic Acid and Polyglycerin-10.

wherein RC(O)- represents the residue of undecylenic acid, and n is 10

Polyglyceryl-6 Ximenia Americana

Seedate

Polyglyceryl-6 Ximenia Americana Seedate is the ester of Polyglycerin-6 and the fatty acids obtained from Ximenia Americana Seed Oil.

wherein RC(O)- represents the residue of the fatty acids obtained from ximenia americana seed oil, and n is 6

Pumpkin Seed Oil Polyglyceryl-4 Esters

Pumpkin Seed Oil Polyglyceryl-4 Esters is the complex mixture of esters formed by the transesterification of Cucurbita Pepo (Pumpkin) Seed Oil and Polyglycerin-4.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Cucurbita Pepo (Pumpkin) Seed Oil, and n is 4


- 30 -



Rice Bran Oil Polyglyceryl-3 Esters Rice Bran Oil Polyglyceryl-3 Esters is the product obtained by the transesterification of Oryza Sativa (Rice) Bran Oil and Polyglycerin-3.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Oryza Sativa (Rice) Bran Oil, and n is 3

Rosa Rubiginosa Seed Oil


Rosa Rubiginosa Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Rosa Rubiginosa Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Rosa Rubiginosa Seed Oil, and n is 6

Safflower Seed Oil Polyglyceryl-6

Esters

Safflower Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Carthamus Tinctorius (Safflower) Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Carthamus Tinctorius (Safflower) Seed Oil, and n is 6

Schinziophyton Rautanenii Kernel

Oil Polyglyceryl-6 Esters

Schinziophyton Rautanenii Kernel Oil Polyglyceryl-6 Esters is the product formed by the transesterification of Schinziophyton Rautanenii Kernel Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Schinziophyton Rautanenii Kernel Oil, and n is 6

Sclerocarya Birrea Seed Oil


Sclerocarya Birrea Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Sclerocarya Birrea Seed Oil with Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Sclerocarya Birrea Seed Oil, and n is 6

Sclerocarya Birrea Seed Oil


Sclerocarya Birrea Seed Oil Polyglyceryl-10 Esters is the product obtained by the transesterification of Sclerocarya Birrea Seed Oil with Polyglycerin-10.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Sclerocarya Birrea Seed Oil, and n is 10


- 31 -



Sesame Oil Polyglyceryl-6 Esters Sesame Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Sesamum Indicum (Sesame) Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Sesamum Indicum (Sesame) Oil, and n is 6

Shea Butter Polyglyceryl-3 Esters Shea Butter Polyglyceryl-3 Esters is the product obtained by the transesterification of Polyglycerin-3 and Butyrospermum Parkii (Shea) Butter.


Shea Butter Polyglyceryl-6 Esters Shea Butter Polyglyceryl-6 Esters is the product obtained by the transesterification of Butyrospermum Parkii (Shea) Butter and Polyglycerin-6.


Soybean Oil Polyglyceryl-6 Esters Soybean Oil Polyglyceryl-6 Esters is the product of the transesterification of Glycine Soja (Soybean) Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Glycine Soja (Soybean) Oil, and n is 6

Sunflower Seed Oil Polyglyceryl-3

Esters

Sunflower Seed Oil Polyglyceryl-3 Esters is the product obtained by the transesterification of Helianthus Annuus (Sunflower) Seed Oil and Polyglycerin-3.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Helianthus Annuus (Sunflower) Seed Oil, and n is 3


- 32 -




Esters




Esters

Sunflower Seed Oil Polyglyceryl-5 Esters is the product obtained by the transesterification of Helianthus Annuus (Sunflower) Seed Oil and a glycerin polymer containing 5 units of glycerin.



Esters




Esters



Sweet Almond Oil Polyglyceryl-4

Esters

1072006-19-9 [generic for n]

Sweet Almond Oil Polyglyceryl-4 Esters is the product obtained by the transesterification of Prunus Amygdalus Dulcis (Sweet Almond) Oil and Polyglycerin-4.



- 33 -



Sweet Almond Oil Polyglyceryl-6

Esters

Sweet Almond Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Prunus Amygdalus Dulcis (Sweet Almond) Oil and Polyglycerin-6.


Theobroma Grandiflorum Seed

Butter Polyglyceryl-6 Esters

Theobroma Grandiflorum Seed Butter Polyglyceryl-6 Esters is the product obtained by the transesterification of Theobroma Grandiflorum Seed Butter and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Theobroma Grandiflorum Seed Butter, and n is 6

Trichilia Emetica Seed Oil


Trichilia Emetica Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Trichilia Emetica Seed Butter and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Trichilia Emetica Seed Butter, and n is 6

Watermelon Seed Oil


Watermelon Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Citrullus Lanatus (Watermelon) Seed Oil with Polyglycerin-6.


Watermelon Seed Oil


Watermelon Seed Oil Polyglyceryl-10 Esters is the product obtained by the transesterification of Citrullus Lanatus (Watermelon) Seed Oil with Polyglycerin-10.



- 34 -



Ximenia Americana Seed Oil


Ximenia Americana Seed Oil Polyglyceryl-6 Esters is the product obtained by the transesterification of Ximenia Americana Seed Oil and Polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Ximenia Americana Seed Oil, and n is 6

Polyglyceryl Multi-esters (i.e., not mono-esters and not “polyesters”)

Macadamia Seed Oil

Polyglyceryl-6 Esters Behenate

Macadamia Seed Oil Polyglyceryl-6 Esters Behenate is the behenic acid ester of the product obtained by the transesterification of macadamia seed oil and polyglycerin-6.

wherein RC(O)- represents the residue of fatty acids derived (via transesterification) from Macadamia Ternifolia Seed Oil, and n is 6

Polyglyceryl-8

Decabehenate/Caprate

Polyglyceryl-8 Decabehenate/Caprate is the decaester of a mixture of Behenic Acid and Capric Acid with a glycerin polymer containing 8 units of glycerin.

wherein RC(O)- represents the residue of capric or behanic acid, and n is 8

Polyglyceryl-8

Decaerucate/Decaisostearate/

Decaricinoleate

Polyglyceryl-8 Decaerucate/Decaisostearate/Decaricinoleate is the decaester of a glycerin polymer containing 8 units of glycerin with a mixture of Erucic Acid, Isostearic Acid and Ricinoleic Acid.

wherein RC(O)- represents the residue of erucic, isostearic, or ricinoleaic acid, and n is 8

Polyglyceryl-10

Decaethylhexanoate

Polyglyceryl-10 Decaethylhexanoate is the decaester of 2-ethylhexanoic acid and Polyglycerin-10.

wherein RC(O)- represents the residue of ethylhexanoic acid, and n is 10


- 35 -



Polyglyceryl-10

Decahydroxystearate

Polyglyceryl-10 Decahydroxystearate is the decaester of Hydroxystearic Acid and Polyglycerin-10.

wherein RC(O)- represents the residue of hydroxystearic acid, and n is 10

Polyglyceryl-10 Decaisostearate Polyglyceryl-10 Decaisostearate is the ester of Polyglycerin-10 and Isostearic Acid.


Polyglyceryl-10 Decalinoleate

68900-96-9

Polyglyceryl-10 Decalinoleate is a decaester of linoleic acid and Polyglycerin-10.

wherein RC(O)- represents the residue of linoleic acid, and n is 10

Polyglyceryl-10 Decamacadamiate Polyglyceryl-10 Decamacadamiate is a decaester of Polyglycerin-10 and the fatty acids derived from macadamia nut oil.

wherein RC(O)- represents the residue of the fatty acids derived from macadamia nut oil, and n is 10

Polyglyceryl-10 Decaoleate

11094-60-3

Polyglyceryl-10 Decaoleate is a decaester of oleic acid and Polyglycerin-10.


Polyglyceryl-10 Decastearate

39529-26-5

Polyglyceryl-10 Decastearate is a decaester of stearic acid and Polyglycerin-10.



- 36 -



Polyglyceryl-3 Dicaprate Polyglyceryl-3 Dicaprate is the diester of capric acid and Polyglycerin-3.

wherein RC(O)- represents the residue of capric acid, and n is 3

Polyglyceryl-6 Dicaprate Polyglyceryl-6 Dicaprate is the diester of Capric Acid and Polyglycerin-6.


Polyglyceryl-5 Dicaprylate

108777-93-1 (generic)

Polyglyceryl-5 Dicaprylate is the diester of Caprylic Acid with a glycerin polymer containing 5 glycerin units.

wherein RC(O)- represents the residue of caprylic acid, and n is 5

Polyglyceryl-3 Dicitrate/Stearate Polyglyceryl-3 Dicitrate/Stearate is the diester of Polyglycerin-3 with a mixture of Citric Acid and Stearic Acid.

wherein RC(O)- represents the residue of citric or stearic acid, and n is 3

Polyglyceryl-3 Dicocoate Polyglyceryl-3 Dicocoate is the diester of Coconut Acid and Polyglycerin-3.


Polyglyceryl-10 Dicocoate Polyglyceryl-10 Dicocoate is the diester of Coconut Acid and Polyglycerin-10.


Polyglyceryl-10 Didecanoate

182015-59-4

Polyglyceryl-10 Didecanoate is the diester of decanoic acid and Polyglycerin-10.

wherein RC(O)- represents the residue of decanoic acid, and n is 10


- 37 -



Polyglyceryl-3 Di-Hydroxystearate

Polyglyceryl-3 Di-Hydroxystearate is the diester of Hydroxystearic Acid and Polyglycerin-3.

wherein RC(O)- represents the residue of Hydroxystearic Acid, and n is 3

Polyglyceryl-2 Diisostearate

63705-03-3 (generic)

67938-21-0

Polyglyceryl-2 Diisostearate is the diester of Isostearic Acid and Diglycerin.

wherein RC(O)- represents the residue of Isostearic Acid, and n is 2


63705-03-3 (generic)

66082-42-6

Polyglyceryl-3 Diisostearate is a diester of Isostearic Acid and Polyglycerin-3.


Polyglyceryl-6 Diisostearate Polyglyceryl-6 Diisostearate is the diester of Isostearic Acid and Polyglycerin-6.



102033-55-6

63705-03-3 (generic)

Polyglyceryl-10 Diisostearate is a diester of Isostearic Acid and Polyglycerin-10.


Polyglyceryl-15 Diisostearate Polyglyceryl-15 Diisostearate is a diester of Isostearic Acid and a glycerin polymer containing 15 glycerin units.



- 38 -



Polyglyceryl-4 Dilaurate Polyglyceryl-4 Dilaurate is the diester of Lauric Acid and Polyglycerin-4.

wherein RC(O)- represents the residue of Lauric Acid, and n is 4

Polyglyceryl-5 Dilaurate Polyglyceryl-5 Dilaurate is the diester of lauric acid and a glycerin polymer containing 5 units of glycerin.


Polyglyceryl-10 Dilaurate Polyglyceryl-10 Dilaurate is the diester of lauric acid and Polyglycerin-10.


Polyglyceryl-10 Dimyristate Polyglyceryl-10 Dimyristate is the diester of myristic acid and Polyglycerin-10.


Polyglyceryl-2 Dioleate

60219-68-3

67965-56-4

Polyglyceryl-2 Dioleate is a diester of oleic acid and Diglycerin.



79665-94-4

Polyglyceryl-3 Dioleate is a diester of oleic acid and Polyglycerin-3.


Polyglyceryl-5 Dioleate Polyglyceryl-5 Dioleate is the diester of Oleic Acid and a glycerin polymer containing 5 units of glycerin.



- 39 -




76009-37-5




33940-99-7



Polyglyceryl-6 Dipalmitate Polyglyceryl-6 Dipalmitate is the diester of Palmitic Acid and Polyglycerin-6.

wherein RC(O)- represents the residue of Palmitic Acid, and n is 6

Polyglyceryl-10 Dipalmitate Polyglyceryl-10 Dipalmitate is the diester of Palmitic Acid and Polyglycerin-10.

wherein RC(O)- represents the residue of Palmitic Acid, and n is 10

Polyglyceryl-2 Distearate

9009-32-9

Polyglyceryl-2 Distearate is the diester of stearic acid and Diglycerin.



9009-32-9 (generic)

94423-19-5

Polyglyceryl-3 Distearate is the diester of stearic acid and Polyglycerin-3.


Polyglyceryl-4 Distearate Polyglyceryl-4 Distearate is a diester of Polyglycerin-4 with Stearic Acid.



- 40 -




34424-97-0

9009-32-9 (generic)

Polyglyceryl-6 Distearate is a diester of stearic acid and Polyglycerin-6.



12764-60-2

9009-32-9 (generic)

Polyglyceryl-10 Distearate is the diester of stearic acid and Polyglycerin-10.


Polyglyceryl-20

Docosabehenate/Isostearate

Polyglyceryl-20 Docosabehenate/Isostearate is the docosaester of Polyglycerin-20 with a mixture of behenic and isostearic acids.

wherein RC(O)- represents the residue of behenic or isostearic acid, and n is 20

Polyglyceryl-20

Docosabehenate/Laurate

Polyglyceryl-20 Docosabehenate/Laurate is the docosaester of Polyglycerin-20 with a mixture of behenic and lauric acids.

wherein RC(O)- represents the residue of behenic or lauric acid, and n is 20

Polyglyceryl-20

Docosabehenate/Oleate

Polyglyceryl-20 Docosabehenate/Oleate is the docosaester of Polyglycerin-20 with a mixture of behenic and oleic acids.

wherein RC(O)- represents the residue of behenic or oleic acid, and n is 20

Polyglyceryl-10 Dodecabehenate Polyglyceryl-10 Dodecabehenate is the dodecaester of behenic acid and Polyglycerin-10.

wherein RC(O)- represents the residue of behenic, and n is 10


- 41 -



Polyglyceryl-10 Dodecacaprate Polyglyceryl-10 Dodecacaprate is the dodecaester of capric acid and Polyglycerin-10.


Polyglyceryl-10 Dodecacaprylate Polyglyceryl-10 Dodecacaprylate is the dodecaester of caprylic acid and Polyglycerin-10.


Polyglyceryl-10 Dodeca-Caprylate/

Caprate

Polyglyceryl-10 Dodeca-Caprylate/Caprate is the dodecaester of a mixture of caprylic and capric acids with Polyglycerin-10.


Polyglyceryl-10

Hepta(Behenate/Stearate)

Polyglyceryl-10 Hepta(Behenate/Stearate) is the heptaester of Polyglycerin-10 with a mixture of Behenic Acid and Stearic Acid.

wherein R- represents hydrogen or the residue of behenic acid and stearic acid, and n is 10

Polyglyceryl-6 Heptacaprylate Polyglyceryl-6 Heptacaprylate is the heptaester of caprylic acid and Polyglycerin-6.

wherein R- represents hydrogen or the residue of caprylic acid, and n is 6

Polyglyceryl-20 Heptacaprylate Polyglyceryl-20 Heptacaprylate is the heptaester of Caprylic Acid and Polyglycerin-20.



- 42 -



Polyglyceryl-20

Heptadecabehenate/Laurate

Polyglyceryl-20 Heptadecabehenate/Laurate is the heptadecaester of Polyglycerin-20 with a mixture of behenic and lauric acids.

wherein R- represents hydrogen or the residue of behenic or lauric acid, and n is 20

Polyglyceryl-10

Heptahydroxystearate

Polyglyceryl-10 Heptahydroxystearate is a heptaester of Hydroxystearic Acid and Polyglycerin-10.

wherein R- represents hydrogen or the residue of hydroxystearic acid, and n is 10

Polyglyceryl-10 Heptaoleate

103175-09-3

Polyglyceryl-10 Heptaoleate is a heptaester of oleic acid and Polyglycerin-10.

wherein R- represents hydrogen or the residue of oleic acid, and n is 10

Polyglyceryl-10 Heptastearate

9009-32-9 (generic)

99126-54-2

Polyglyceryl-10 Heptastearate is the heptaester of stearic acid and Polyglycerin-10.

wherein R- represents hydrogen or the residue of stearic acid, and n is 10

Polyglyceryl-20 Hexacaprylate Polyglyceryl-20 Hexacaprylate is the hexaester of Caprylic Acid and Polyglycerin-20.


Polyglyceryl-10 Hexaerucate Polyglyceryl-10 Hexaerucate is the hexaester of Polyglycerin-10 and Erucic Acid.

wherein R- represents hydrogen or the residue of erucic acid, and n is 10

Polyglyceryl-10 Hexaisostearate Polyglyceryl-10 Hexaisostearate is the hexaester of Polyglycerin-10 and isostearic acid.

wherein R- represents hydrogen or the residue of isostearic acid, and n is 10


- 43 -



Polyglyceryl-6 Hexaoleate

95482-05-6

Polyglyceryl-6 Hexaoleate is a hexaester of oleic acid and Polyglycerin-6.


Polyglyceryl-10 Hexaoleate

65573-03-7

Polyglyceryl-10 Hexaoleate is the hexaester of Oleic Acid and Polyglycerin-10.


Polyglyceryl-5 Hexastearate Polyglyceryl-5 Hexastearate is the hexaester of stearic acid and a glycerin polymer containing 5 units of glycerin.


Polyglyceryl-6 Hexastearate Polyglyceryl-6 Hexastearate is the hexaester of stearic acid and Polyglycerin-6.


Polyglyceryl-10 Mono/Dioleate Polyglyceryl-10 Mono/Dioleate is a mixture of mono- and diesters of oleic acid and Polyglycerin-10.


Polyglyceryl-10 Nonaerucate

155808-79-0

Polyglyceryl-10 Nonaerucate is the nonaester of Erucic Acid and Polyglycerin-10.


Polyglyceryl-10 Nonaisostearate Polyglyceryl-10 Nonaisostearate is the nonaester of Polyglycerin-10 and Isostearic Acid.



- 44 -



Polyglyceryl-6 Octacaprylate Polyglyceryl-6 Octacaprylate is the octaester of Polyglycerin-6 and caprylic acid.


Polyglyceryl-20

Octadecabehenate/Laurate

Polyglyceryl-20 Octadecabehenate/Laurate is the octadecaester of Polyglycerin-20 and a mixture of behenic and lauric acids.

wherein R- represents hydrogen or the residue of behenic or lauric acid, and n is 20

Polyglyceryl-20 Octaisononanoate Polyglyceryl-20 Octaisononanoate is the octaester of isononanoic acid and Polyglycerin-20.

wherein R- represents hydrogen or the residue of isononanoic acid, and n is 20

Polyglyceryl-6 Octastearate Polyglyceryl-6 Octastearate is the octaester of stearic acid and Polyglycerin-6.


Polyglyceryl-6 Pentacaprylate Polyglyceryl-6 Pentacaprylate is the pentaester of caprylic acid and Polyglycerin-6.


Polyglyceryl-10 Pentacaprylate Polyglyceryl-10 Pentacaprylate is the pentaester of Caprylic Acid and Polyglycerin-10.



- 45 -



Polyglyceryl-3

Pentacaprylate/Caprate

Polyglyceryl-3 Pentacaprylate/Caprate is the pentaester of a mixture of Caprylic Acid and Capric Acid with Polyglycerin-3.

wherein R- represents hydrogen or the residue of capric or caprylic acid, and n is 3

Polyglyceryl-10

Pentahydroxystearate

Polyglyceryl-10 Pentahydroxystearate is the pentaester of hydroxystearic acid and Polyglycerin-10.

wherein R- represents hydrogen or the residue of hydroxystearic acid, and n is 10

Polyglyceryl-10 Pentaisostearate Polyglyceryl-10 Pentaisostearate is the pentaester of isostearic acid and Polyglycerin-10.


Polyglyceryl-10 Pentalaurate Polyglyceryl-10 Pentalaurate is the pentaester of Lauric Acid and Polyglycerin-10.

wherein R- represents hydrogen or the residue of lauric acid, and n is 10

Polyglyceryl-10 Pentalinoleate Polyglyceryl-10 Pentalinoleate is the pentaester of Linoleic Acid and Polyglycerin-10.

wherein R- represents hydrogen or the residue of linoleic acid, and n is 10

Polyglyceryl-5 Pentamyristate Polyglyceryl-5 Pentamyristate is the pentaester of myristic acid and a glycerin polymer containing 5 units of glycerin.

wherein R- represents hydrogen or the residue of myristic acid, and n is 5

Polyglyceryl-4 Pentaoleate

103230-29-1

Polyglyceryl-4 Pentaoleate is the pentaester of Oleic Acid and Polyglycerin-4.



- 46 -




104934-17-0

Polyglyceryl-6 Pentaoleate is the pentaester of oleic acid and Polyglycerin-6.



86637-84-5

Polyglyceryl-10 Pentaoleate is the pentaester of oleic acid and Polyglycerin-10.


Polyglyceryl-3 Pentaolivate Polyglyceryl-3 Pentaolivate is the pentaester of Polyglycerin-3 and Olive Acid.

wherein RC(O)- represents the residue of olive acid, and n is 3

Polyglyceryl-4

Pentapalmitate/Stearate

Polyglyceryl-4 Pentapalmitate/Stearate is the pentaester of a mixture of Palmitic Acid and Stearic Acid with Polyglycerin-4.

wherein R- represents hydrogen or the residue of palmitic or stearic acid, and n is 4

Polyglyceryl-3 Pentaricinoleate Polyglyceryl-3 Pentaricinoleate is the pentaester of Ricinoleic Acid and Polyglycerin-3.



wherein R- represents hydrogen or the residue of ricinoleic acid, and n is 6


wherein R- represents hydrogen or the residue of ricinoleic acid, and n is 10


- 47 -



Polyglyceryl-4 Pentastearate

99570-00-0

Polyglyceryl-4 Pentastearate is the pentaester of Stearic Acid and Polyglycerin-4.



9009-32-9 (generic)

99734-30-2

Polyglyceryl-6 Pentastearate is the pentaester of stearic acid and Polyglycerin-6.



9009-32-9 (generic)

95461-64-6

Polyglyceryl-10 Pentastearate is a pentaester of stearic acid and Polyglycerin-10.


Polyglyceryl-2 Sesquicaprylate Polyglyceryl-2 Sesquicaprylate is a mixture of mono- and diesters of caprylic acid and Diglycerin.


Polyglyceryl-6 Sesquicaprylate

108777-93-1 (generic)

946492-22-4 (generic)

946492-23-5 (generic)

Polyglyceryl-6 Sesquicaprylate is a mixture of mono- and diesters of Caprylic Acid and Polyglycerin-6.


Polyglyceryl-2 Sesquiisostearate Polyglyceryl-2 Sesquiisostearate is a mixture of mono and diesters of Isostearic Acid and Diglycerin.


Polyglyceryl-6 Sesquiisostearate Polyglyceryl-6 Sesquiisostearate is a mixture of mono- and diesters of Isostearic Acid and Polyglycerin-6.



- 48 -



Polyglyceryl-2 Sesquioleate Polyglyceryl-2 Sesquioleate is a mixture of mono and diesters of oleic acid and Diglycerin.


Polyglyceryl-2 Sesquistearate

9009-32-9 (generic)

Polyglyceryl-2 Sesquistearate is a mixture of mono- and diesters of stearic acid and Diglycerin.

wherein R- represents hydrogen or the residue of stearate acid, and n is 2

Polyglyceryl-6 Sesquistearate

112939-69-2

Polyglyceryl-6 Sesquistearate is a mixture of mono- and diesters of stearic acid and Polyglycerin-6.


Polyglyceryl-10 Sesquistearate Polyglyceryl-10 Sesquistearate is a mixture of mono- and diesters of stearic acid and Polyglycerin-10.


Polyglyceryl-6 Tetrabehenate Polyglyceryl-6 Tetrabehenate is the tetraester of Behenic Acid and Polyglycerin-6.

wherein R- represents hydrogen or the residue of behenic acid, and n is 6

Polyglyceryl-2 Tetrabehenate/

Macadamiate/Sebacate

Polyglyceryl-2 Tetrabehenate/Macadamiate/Sebacate is the tetraester of a mixture of behenic, sebacic and macadamia acids with a dimer of glycerin.

wherein RC(O)- represents the residue of behenic, sebacic, or macadamia acid, and n is 2

Polyglyceryl-6 Tetracaprylate Polyglyceryl-6 Tetracaprylate is the tetraester of caprylic acid and Polyglycerin-6.



- 49 -



Polyglyceryl-10 Tetradecanedioate Polyglyceryl-10 Tetradecanedioate is the ester of tetradecanedioic acid and Polyglycerin-10.

wherein R- represents hydrogen or the residue of tetradecanoic acid, and n is 10

Polyglyceryl-2 Tetraisostearate

121440-30-0

Polyglyceryl-2 Tetraisostearate is the tetraester of isostearic acid and a dimer of glycerin.


Polyglyceryl-10 Tetralaurate Polyglyceryl-10 Tetralaurate is the tetraester of lauric acid and Polyglycerin-10.


Polyglyceryl-2 Tetraoleate Polyglyceryl-2 Tetraoleate is the tetraester of oleic acid and Diglycerin.


Polyglyceryl-6 Tetraoleate

128774-95-8

Polyglyceryl-6 Tetraoleate is the tetraester of Oleic Acid and Polyglycerin-6.


Polyglyceryl-10 Tetraoleate

34424-98-1

Polyglyceryl-10 Tetraoleate is a tetraester of oleic acid and Polyglycerin-10.


Polyglyceryl-2 Tetrastearate

72347-89-8

9009-32-9 (generic)

Polyglyceryl-2 Tetrastearate is the tetraester of stearic acid and Diglycerin.



- 50 -



Polyglyceryl-5 Tribehenate Polyglyceryl-5 Tribehenate is the triester of behenic acid and a glycerin polymer containing 5 units of glycerin.

wherein R- represents hydrogen or the residue of behenic acid, and n is 5

Polyglyceryl-6 Tricaprylate Polyglyceryl-6 Tricaprylate is the triester of Caprylic Acid and Polyglycerin-6.


Polyglyceryl-10 Tricocoate Polyglyceryl-10 Tricocoate is the triester of Coconut Acid and Polyglycerin-10.

wherein R- represents hydrogen or the residue of coconut acid, and n is 10

Polyglyceryl-10 Tridecanoate

217782-56-4

Polyglyceryl-10 Tridecanoate is the triester of decanoic acid and Polyglycerin-10.

wherein R- represents hydrogen or the residue of decanoic acid, and n is 10

Polyglyceryl-10 Trierucate Polyglyceryl-10 Trierucate is the triester of Polyglycerin-10 and Erucic Acid.


Polyglyceryl-2 Triisostearate

120486-24-0

Polyglyceryl-2 Triisostearate is the triester of isostearic acid and Diglycerin.


Polyglyceryl-3 Triisostearate

66082-43-7

Polyglyceryl-3 Triisostearate is the triester of Isostearic Acid and Polyglycerin-3.



- 51 -



Polyglyceryl-5 Triisostearate Polyglyceryl-5 Triisostearate is the triester of Isostearic Acid and a glycerin polymer containing 5 units of glycerin.


Polyglyceryl-10 Triisostearate Polyglyceryl-10 Triisostearate is the triester of Polyglycerin-10 and Isostearic Acid.


Polyglyceryl-10 Trilaurate Polyglyceryl-10 Trilaurate is the triester of lauric acid and Polyglycerin-10.


Polyglyceryl-5 Trimyristate Polyglyceryl-5 Trimyristate is the triester of myristic acid and a glycerin polymer containing 5 units of glycerin.

wherein R- represents hydrogen or the residue of myristic acid, and n is 5

Polyglyceryl-5 Trioleate Polyglyceryl-5 Trioleate is the triester of oleic acid and a glycerin polymer containing 5 units of glycerin.


Polyglyceryl-10 Trioleate

102051-00-3

Polyglyceryl-10 Trioleate is the triester of oleic acid and Polyglycerin-10.


Polyglyceryl-3 Triolivate Polyglyceryl-3 Triolivate is the triester of Polyglycerin-3 and Olive Acid.

wherein R- represents hydrogen or the residue of olive acid, and n is 3


- 52 -



Polyglyceryl-4 Tristearate

99734-29-9

Polyglyceryl-4 Tristearate is the triester of Stearic Acid and Polyglycerin-4.



9009-32-9 (generic)

Polyglyceryl-5 Tristearate is the triester of stearic acid and a glycerin polymer containing 5 units of glycerin.



71185-87-0

9009-32-9 (generic)

Polyglyceryl-6 Tristearate is the triester of stearic acid and Polyglycerin-6.



12709-64-7

9009-32-9 (generic)

Polyglyceryl-10 Tristearate is the triester of stearic acid and Polyglycerin-10.


Triisostearoyl Polyglyceryl-3 Dimer

Dilinoleate

Triisostearoyl Polyglyceryl-3 Dimer Dilinoleate is the diester of Dilinoleic Acid and Polyglyceryl-3 Triisostearate.

wherein R- represents the residue of isostearic acid or dilinoleic acid, and n is 3


- 53 -

Table 2. Other structure types from prior CIR reports, proposed for EXCLUSION from this report

IJT 23 (Suppl. 2:55-94,)2004

Some Glyceryl Stearates from this issue of IJT are included in Table 1, but the

ingredients recited below appear to be structurally too dissimilar. Glyceryl Polyacrylate

104365-75-5

Glyceryl Polyacrylate is the ester of Glycerin and Polyacrylic Acid.

Glyceryl/Sorbitol

Oleate/Hydroxystearate

Glyceryl/Sorbitol Oleate/Hydroxystearate is the mixed esterification product of glycerin and sorbitol with hydroxystearic and oleic acids.

Glyceryl Thiopropionate

67874-65-1

Glyceryl Thiopropionate is the organic compound that conforms to the formula

Glyceryl Collagenate

Glyceryl Collagenate is the ester of glycerin and Collagen. (Collagen is the protein found in cartilage and other connective tissues in animals.)

wherein RC(O)- represents the residue of collagen

IJT 28(Suppl. 1):68-133, 2009 While technically a glyceryl ester, the thio-group in the following ingredient is too dissimilar from the alkyl chains of the Glyceryl Esters.

Glyceryl Thioglycolate

30618-84-9

Glyceryl Thioglycolate is the monoester of glycerin and Thioglycolic Acid. It



Monoglyceryl Monoesters (RR of Glyceryl Stearate and Glyceryl Stearate SE)

1982: Panel concluded that glyceryl stearate and glyceryl stearate SE are safe for topical application to humans 1986: Panel concluded glyceryl oleate is safe as a cosmetic ingredient in the present practices of use and concentration; the conclusion was reaffirmed in 2004 1999: Panel concluded data were insufficient to determine safety of Glyceryl Ricinoleate 2007: Panel concluded Glyceryl Ricinoleate and Glyceryl Ricinoleate SE were safe as a cosmetic ingredient in the practices of use and concentrations 2004: Panel concluded a group of glyceryl monoesters were safe as a cosmetic ingredient in the practices of use and concentrations


Monoglyceryl Monoesters (new data only) – Sept 2015 – Monice Fiume Re

port

ed U

se -

curr

ent

Met

hod

of M

fg

Impu

riti

es

Toxi

coki

neti

cs

Der

mal

Pen

etra

tion

Anim

al T

ox –

Acu

te,

Der

mal

An

imal

Tox

– A

cute

, O

ral

Anim

al T

ox, A

cute

, In

hala

tion

An

imal

Tox

– R

ptd

D

ose,

Der

mal

An

imal

Tox

, Rpt

d D

ose,

O

ral

Anim

al T

ox –

Rpt

d D

ose,

Inha

lati

on

Repr

o/D

ev T

oxic

ity

Geno

toxi

city

Carc

inog

enic

ity

Der

mal

Irr/

Sens

Case

Rep

orts

Ocu

lar

Irri

tati

on

Muc

ous

Mem

bran

e Ir

r

Glyceryl Stearate X X X Glyceryl Stearate SE X Glyceryl Acetate X Glyceryl Adipate Glyceryl Alginate Glyceryl Arachidate Glyceryl Behenate X X X X Glyceryl Caprate X Glyceryl Caprylate X Glyceryl Caprylate/Caprate X Glyceryl Citrate/Lactate/Linoleate/Oleate X Glyceryl Cocoate X Glyceryl Cocoate/Citrate/Lactate Glyceryl Erucate Glyceryl Ethylhexanoate Glyceryl Ethylhexanoate/Stearate/ Adipate X Glyceryl Heptanoate Glyceryl Hydrogenated Rapeseedate Glyceryl Hydrogenated Rosinate X X X X Glyceryl Hydrogenated Soyate Glyceryl Hydroxystearate X Glyceryl Isopalmitate Glyceryl Isostearate X Glyceryl Isotridecanoate/Stearate/Adipate X Glyceryl Lanolate X Glyceryl Laurate X X Glyceryl Laurate SE


Monoglyceryl Monoesters (new data only) – Sept 2015 – Monice Fiume Re

port

ed U

se -

curr

ent

Met

hod

of M

fg

Impu

riti

es

Toxi

coki

neti

cs

Der

mal

Pen

etra

tion

Anim

al T

ox –

Acu

te,

Der

mal

An

imal

Tox

– A

cute

, O

ral

Anim

al T

ox, A

cute

, In

hala

tion

An

imal

Tox

– R

ptd

D

ose,

Der

mal

An

imal

Tox

, Rpt

d D

ose,

O

ral

Anim

al T

ox –

Rpt

d D

ose,

Inha

lati

on

Repr

o/D

ev T

oxic

ity

Geno

toxi

city

Carc

inog

enic

ity

Der

mal

Irr/

Sens

Case

Rep

orts

Ocu

lar

Irri

tati

on

Muc

ous

Mem

bran

e Ir

r

Glyceryl Laurate/Oleate Glyceryl Linoleate X Glyceryl Linolenate X Glyceryl Montanate Glyceryl Oleate X X Glyceryl Oleate SE X Glyceryl Oleate/Elaidate X Glyceryl Olivate Glyceryl Palmitate X Glyceryl Palmitate/Stearate X Glyceryl Palmitoleate Glyceryl Pentadecanoate Glyceryl Ricinoleate X Glyceryl Ricinoleate SE X Glyceryl Rosinate X X X X X X X X Glyceryl Stearate/Malate X Glyceryl Tallowate Glyceryl Undecylenate


PREVIOUS REPORTS of MON OGLYCERYL MONOESTERS Im

puri

ties

/Com

posi

tion

Toxi

coki

neti

cs

Der

mal

Abs

orpt

ion

Anim

al T

ox –

Acu

te,

Der

mal

Anim

al T

ox –

Acu

te, O

ral

Anim

al T

ox, A

cute

, Inh

al.

Anim

al T

ox –

Rpt

d D

ose,

D

erm

Anim

al T

ox, R

ptd

Dos

e,

Ora

l

Anim

al T

ox –

Rpt

d D

ose,

In

hal

Repr

o/D

ev T

oxic

ity

Geno

toxi

city

Carc

inog

enic

ity

Der

mal

Irr/

Sens

Ocu

lar

Irri

tati

on

Muc

ous

Mem

bran

e Ir

r

Phot

otox

icit

y

GLYCERYL STEARATE AND GLYCERYL STEARATE SE - 1982

Glyceryl Stearate X X X X X X X

Glyceryl Stearate SE X X X X GLYCERYL OLEATE - 1986 Glyceryl Oleate X X X X X X X X X GLYCERYL RICINOLEATE - 1988 Glyceryl Ricinoleate X X X X X X X RICINUS COMMUNIS (CASTOR) SEEL OIL - 2007 Glyceryl Ricinoleate X Glyceryl Ricinoleate SE GLYCERYL MONOESTERS - 2004 Glyceryl Adipate Glyceryl Alginate Glyceryl Arachidate Glyceryl Behenate X Glyceryl Caprate X X Glyceryl Caprylate X Glyceryl Caprylate/Caprate Glyceryl Citrate/Lactate/Linoleate/Oleate X X X X X Glyceryl Cocoate Glyceryl Erucate Glyceryl Hydrogenated Rosinate X X Glyceryl Hydrogenated Soyate X Glyceryl Hydroxystearate


PREVIOUS REPORTS of MON OGLYCERYL MONOESTERS Im

puri

ties

/Com

posi

tion

Toxi

coki

neti

cs

Der

mal

Abs

orpt

ion

Anim

al T

ox –

Acu

te,

Der

mal

Anim

al T

ox –

Acu

te, O

ral

Anim

al T

ox, A

cute

, Inh

al.

Anim

al T

ox –

Rpt

d D

ose,

D

erm

Anim

al T

ox, R

ptd

Dos

e,

Ora

l

Anim

al T

ox –

Rpt

d D

ose,

In

hal

Repr

o/D

ev T

oxic

ity

Geno

toxi

city

Carc

inog

enic

ity

Der

mal

Irr/

Sens

Ocu

lar

Irri

tati

on

Muc

ous

Mem

bran

e Ir

r

Phot

otox

icit

y

Glyceryl Isopalmitate Glyceryl Isostearate X X X X Glyceryl Isotridecanoate/Stearate/Adipate Glyceryl Lanolate Glyceryl Laurate X X X X X X X Glyceryl Laurate SE Glyceryl Laurate/Oleate Glyceryl Linoleate X Glyceryl Linolenate X Glyceryl Montanate Glyceryl Oleate X Glyceryl Oleate SE Glyceryl Oleate/Elaidate X Glyceryl Palmitate X Glyceryl Palmitate/Stearate X Glyceryl Palmitoleate X Glyceryl Pentadecanoate Glyceryl Rosinate X X X X X Glyceryl Tallowate Glyceryl Undecylenate


CAS No. PrevRev in Use NTIS FDA/CFR NTP ECHA HPVIS IUCLID/SIDS EU NICNAS Web Glyceryl Stearate FCC/NF; RIFM

11099-07-3 123-94-4

31566-31-1 85666-92-8

1982 VCRP PCPC

X no X (for 31566-31-1)

no X X no

Glyceryl Stearate SE 11099-07-3 85666-92-8

1982 VCRP PCPC

no no no X X no

Glyceryl Acetate 26446-35-5 --- --- X X preR no no X no Glyceryl Adipate 26699-71-8 2004 --- no no preR no no X no Glyceryl Alginate ----- 2004 --- no no no no no X no Glyceryl Arachidate 30208-87-8

50906-68-8 2004 --- no no no no no X no

Glyceryl Behenate check FCC; NF

6916-74-1 77538-19-3 30233-64-8

2004 VCRP PCPC

X X (for 77538-19-3)

X no

Glyceryl Caprate 11139-88-1 26402-22-2

2004 VCRP PCPC

X no preR no no X no

Glyceryl Caprylate 26402-26-6 2004 VCRP PCPC


Glyceryl Caprylate/Caprate ----- 2004 VCRP X no no no no X no Glyceryl Citrate/Lactate/Linoleate/Oleate ----- 2004 PCPC no no no no no X no Glyceryl Cocoate 61789-05-7 2004 VCRP

PCPC X no preR no no X no

Glyceryl Cocoate/Citrate/Lactate ----- --- --- no no no no no X no Glyceryl Erucate 28063-42-5 2004 --- X no preR no no X no Glyceryl Ethylhexanoate ----- --- --- no no no no no X no Glyceryl Ethylhexanoate/Stearate/ Adipate ----- --- VCRP

PCPC no no no no no X no

Glyceryl Heptanoate 26402-24-4 --- --- no no no no no X no Glyceryl Hydrogenated Rapeseedate ----- --- --- X no no no no X no Glyceryl Hydrogenated Rosinate FCC

----- 2004 VCRP PCPC

X no no no no X no

Glyceryl Hydrogenated Soyate ----- 2004 --- X no no no no X no Glyceryl Hydroxystearate 1323-42-8 2004 VCRP


Glyceryl Isopalmitate ----- 2004 --- X no no no no X no Glyceryl Isostearate 61332-02-3

66085-00-5 2004 VCRP


Glyceryl Isotridecanoate/Stearate/Adipate ----- 2004 VCRP no no no no no X no Glyceryl Lanolate ----- 2004 VCRP no no no no no X no Glyceryl Laurate 142-18-7

27215-38-9 37318-95-9

2004 VCRP PCPC

X no X (142-18-7)

no no X no

Glyceryl Laurate SE ----- 2004 --- no no no no no X no Glyceryl Laurate/Oleate ----- 2004 --- X no preR no no X no Glyceryl Linoleate 2277-28-3

26545-74-4 37348-65-5

2004 VCRP PCPC

X no preR no no X X

Glyceryl Linolenate 18465-99-1 56554-41-7

2004 VCRP PCPC



CAS No. PrevRev in Use NTIS FDA/CFR NTP ECHA HPVIS IUCLID/SIDS EU NICNAS Web Glyceryl Montanate 68476-38-0

71035-02-4 2004 --- no no preR no no X no

Glyceryl Oleate 111-03-5 161403-66-3 25496-72-4 37220-82-9 68424-61-3

1986; RR not open

2004

VCRP PCPC

X no preR no X (glycerides)

X no

Glyceryl Oleate SE ----- 2004 --- no no no no no X no Glyceryl Oleate/Elaidate ----- 2004 VCRP no no no no no X no Glyceryl Olivate ----- --- --- no no no no no X LaurOliv Glyceryl Palmitate 26657-96-5

542-44-9 2004 VCRP X no preR no no X no

Glyceryl Palmitate/Stearate FCC

68002-71-1 2004 --- X no X no no X no

Glyceryl Palmitoleate ----- 2004 --- X no no no no X no Glyceryl Pentadecanoate 122636-37-7 2004 --- no no no no no X no Glyceryl Ricinoleate 1323-38-2

141-08-2 5086-52-2

1998 2007

VCRP PCPC


Glyceryl Ricinoleate SE --- 2007 PCPC no no no no no X no Glyceryl Rosinate 8050-31-5 2004 VCRP

PCPC X no X X no X no

Glyceryl Stearate/Malate ----- 2004 PCPC no no no no no X no Glyceryl Tallowate ----- 2004 --- no no no no no X no Glyceryl Undecylenate 123759-97-7

62285-15-8 2004 VCRP

PCPC no no preR no no X no

X – indicates data were available PubMed (August 4, 2015): All CAS No.: 11099-07-3 OR 111-03-5 OR 11139-88-1 OR 122636-37-7 OR 123759-97-7 OR 123-94-4 OR 1323-38-2 OR 1323-42-8 OR 141-08-2 OR 142-18-7 OR 161403-66-3 OR 18465-99-1 OR 2277-28-3 OR 25496-72-4 OR 26402-22-2 OR 26402-24-4 OR 26402-26-6 OR 26446-35-5 OR 26545-74-4 OR 26657-96-5 OR 26699-71-8 OR 27215-38-9 OR 28063-42-5 OR 30208-87-8 OR 30233-64-8 OR 31566-31-1 OR 37220-82-9 OR 37318-95-9 OR 37348-65-5 OR 5086-52-2 OR 50906-68-8 OR 542-44-9 OR 56554-41-7 OR 61332-02-3 OR 61789-05-7 OR 62285-15-8 OR 66085-00-5 OR 68002-71-1 OR 68424-61-3 OR 68476-38-0 OR 6916-74-1 OR 71035-02-4 OR 77538-19-3 OR 8050-31-5 OR 85666-92-8 Glyceryl Stearate: ("1980"[Date - Completion] : "3000"[Date - Completion]) AND ((123-94-4[EC/RN Number]) OR 11099-07-3[EC/RN Number]) OR 31566-31-1) OR (85666-92-8 [EC/RN Number]) OR (GLYCERYL AND STEARATE) OR (glycerol AND stearate)))) – 289/3 useful


2004 Report Ingredients – by name: GLYCERYL AND (ADIPATE OR ALGINATE OR BEHENATE OR CAPRATE OR CAPRYLATE OR (CAPRATE AND CAPRYLATE) OR CITRATE OR COCOATE OR ELAIDATE OR ERUCATE OR ROSINATE OR (HYDROGENATED AND SOYATE) OR HYDROXYSTEARATE OR ISOPALMITATE OR ISOSTEARATE OR ISOTRIDECANOATE OR LACTATE OR LANOLATE OR LAURATE OR LINOLEATE OR LINOLENATE OR MONTANATE OR PALMITATE OR PALMITOLEATE OR PENTADECANOATE OR RICINOLEATE OR ROSINATE OR TALLOWATE OR UNDECYLENATE) – 331 hits/7 useful

2004 Report Ingredients: (("2000"[Date - Completion] : "3000"[Date - Completion]) AND (((26699-71-8[EC/RN Number]) OR (30208-87-8[EC/RN Number]) OR (50906-68-8[EC/RN Number]) OR (6916-74-1[EC/RN Number]) OR (77538-19-3[EC/RN Number]) OR (30233-64-8[EC/RN Number]) OR (11139-88-1[EC/RN Number]) OR (26402-22-2[EC/RN Number]) OR (26402-26-6[EC/RN Number]) OR (61789-05-7[EC/RN Number]) OR (28063-42-5[EC/RN Number]) OR (1323-42-8[EC/RN Number]) OR (61332-02-3[EC/RN Number]) OR (66085-00-5[EC/RN Number]) OR (142-18-7[EC/RN Number]) OR (27215-38-9[EC/RN Number]) OR (37318-95-9[EC/RN Number]) OR (2277-28-3[EC/RN Number]) OR (26545-74-4[EC/RN Number]) OR (37348-65-5[EC/RN Number]) OR (18465-99-1[EC/RN Number]) OR (56554-41-7[EC/RN Number]) OR (68476-38-0[EC/RN Number]) OR (71035-02-4[EC/RN Number]) OR (26657-96-5[EC/RN Number]) OR (542-44-9[EC/RN Number]) OR (68002-71-1[EC/RN Number]) OR (122636-37-7[EC/RN Number]) OR (8050-31-5[EC/RN Number]) OR (123759-97-7[EC/RN Number]) OR (62285-15-8[EC/RN Number])) – 119 hits/2 useful Glycerol Oleate ("1984"[Date - Completion] : "3000"[Date - Completion]) AND ((111-03-5[EC/RN Number] OR 161403-66-3[EC/RN Number] OR 25496-72-4[EC/RN Number] OR 37220-82-9[EC/RN Number] OR 68424-61-3[EC/RN Number]) OR ((Glycerol OR Glyceryl) AND oleate)) – 1306 hits/9 useful Glycerol Ricinoleate: ("2005"[Date - Completion] : "3000"[Date - Completion]) AND ((1323-38-2[EC/RN Number]) OR 141-08-2[EC/RN Number]) OR (5086-52-2[EC/RN Number]) OR ((GLYCERYL OR GLYCEROL) AND RICINOLEATE)) – 16 hits/1 useful Not Previously Reviewed: 26446-35-5[EC/RN Number] OR (GLYCERYL AND ACETATE) – 103 hits/1 useful GLYCERYL AND COCOATE AND CITRATE AND LACTATE – 1 hit (CIR report) GLYCERYL AND (COCOATE OR CITRATE OR LACTATE ) – 81 hits/0 useful (GLYCERYL AND ETHYLHEXANOATE) OR (GLYCERYL AND RAPESEEDATE) OR (GLYCERYL AND OLIVATE) – 2 hits/0 useful (GLYCERYL AND HEPTANOATE) OR 26402-24-4[EC/RN Number] – 2 hits/0 useful SciFinder (Aug 5, 2015) – KMP file created Glyceryl monoesters – 31 hits/1 additional Glyceryl esters – 84 hits/0 useful


Amended Safety Assessment of Monoglyceryl Monoesters as Used in Cosmetics

Status: Re-Review for Panel Review Release Date: August 28, 2015 Panel Meeting Date: September 21-22, 2015 The 2015 Cosmetic Ingredient Review Expert Panel members are: Chairman, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D., Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is Lillian J. Gill, D.P.A. This safety assessment was prepared by Monice M. Fiume, Assistant Director/Senior Scientific Analyst/Writer and Bart Heldreth, Ph.D., Chemist.

© Cosmetic Ingredient Review 1620 L Street, NW, Suite 1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651 ♢ fax 202.331.0088 ♢

[email protected]


mailto:[email protected]

INTRODUCTION In 1982, the Cosmetic Ingredient Review (CIR) Expert Panel (Panel) published the Final Report on the Safety Assessment of Glyceryl Stearate and Glyceryl Stearate SE; based on the data presented in that assessment, that Panel concluded that glyceryl stearate and glyceryl stearate SE are safe for topical application to humans.1 In accordance with its Procedures, CIR evaluates the conclusions of previously-issued reports every 15 years to determine whether or not the conclusion should be reaffirmed. A re-review of glyceryl stearate has not been conducted; therefore, one is now being initiated.

Numerous additional monoglyceryl monoesters have also been previously reviewed by CIR. These monoglyceryl mono-esters are structurally-constituted of the esterification products of glycerin and fatty acids. Additionally, almost all of these ingredients are skin conditioning agents.2 Therefore, because of the structural and functional similarities, the following are the monoglyceryl monoesters proposed to be included, and the existing conclusions:

• Glyceryl Oleate – reviewed in 1986, and found to be safe as a cosmetic ingredient in the present practices of use and concentration;3 a re-review was conducted in 2004, and the conclusion was reaffirmed

• Glyceryl Ricinoleate - first reviewed in 1988, and at that time the Panel concluded the data were insufficient to determine safety;4 in 2007, it was reviewed as part of a larger group of ingredients and found safe as a cosmetic ingredient in the practices of use and concentrations.5

• Glyceryl Ricinoleate SE - also reviewed as part of a larger group of ingredients in 2007, and found safe as a cosmetic ingredient in the practices of use and concentrations.5

• Glyceryl Monoesters – in 2004, the following glyceryl monoesters were determined to be safe as cosmetic ingredients in the present practices of use and concentration:6

Glyceryl Adipate Glyceryl Alginate Glyceryl Arachidate Glyceryl Behenate Glyceryl Caprate Glyceryl Caprylate Glyceryl Caprylate/Caprate Glyceryl Citrate/Lactate/Linoleate/Oleate Glyceryl Cocoate Glyceryl Erucate Glyceryl Hydrogenated Rosinate Glyceryl Hydrogenated Soyate Glyceryl Hydroxystearate Glyceryl Isopalmitate Glyceryl Isostearate Glyceryl Isotridecanoate/Stearate/Adipate Glyceryl Lanolate

Glyceryl Laurate Glyceryl Laurate SE Glyceryl Laurate/Oleate Glyceryl Linoleate Glyceryl Linolenate Glyceryl Montanate Glyceryl Oleate Glyceryl Oleate SE Glyceryl Oleate/Elaidate Glyceryl Palmitate Glyceryl Palmitate/Stearate Glyceryl Palmitoleate Glyceryl Pentadecanoate Glyceryl Rosinate Glyceryl Stearate/Maleate Glyceryl Tallowate Glyceryl Undecylenate

Please note: Glyceryl arachidonate was also included in the 2004 safety assessment of glyceryl monoesters; however, the data were insufficient to support the safety of this ingredient, and therefore glyceryl arachidonate is not part of the current re-review.

Furthermore, there are several monoglyceryl monoesters included in the International Cosmetic Ingredient Dictionary that have not yet been reviewed. It is proposed that these 8 ingredients also be included as part of this safety assessment:

Glyceryl Acetate Glyceryl Cocoate/Citrate/Lactate Glyceryl Ethylhexanoate Glyceryl Ethylhexanoate/Stearate/Adipate

Glyceryl Heptanoate Glyceryl Hydrogenated Rapeseedate Glyceryl Olivate Glyceryl Stearate/Malate

Additional note: In 2004, the International Cosmetic Ingredient Dictionary included the name glyceryl stearate/maleate as an ingredient. That ingredient was subsequently included in the 2004 assessment of glyceryl monoester. However, that was an error and glyceryl stearate/maleate is not a cosmetic ingredient. Glyceryl stearate/malate is an ingredient, and will be included in the re-review. (The Panel published a safety assessment on malic acid in 2001; the Panel concluded malic acid was safe for use as a pH adjuster in cosmetic formulations, and the data were insufficient to determine the safety for any other functions.)7


An alphabetical listing of the 45 monoglyceryl monoesters that are proposed for inclusion in one safety assessment is provided in Table 1, and these ingredients are defined in Table 2.

Excerpts from the summaries of the reports on the previously reviewed monoglyceryl monoesters are disseminated through-out the text of this re-review document, as appropriate, and are identified by italicized text. (This information is not included in the tables or the summary section.)

As stated earlier, these monoesters all share a glycerin core. The Panel evaluated the safety of glycerin as used in cosmetics in 2014, concluding that glycerin is safe in cosmetics in the present practices of use and concentration described in the safety assessment.8 Many of the fatty acid components of these monoesters have also been reviewed by CIR. A listing of those that have been reviewed, and the associated conclusions, are provided in Table 3.5,7,9-19 (The full reports can be found on the CIR website: http://www.cir-safety.org/ingredients) CIR will be concurrently reviewing the safety of Polyglyceryl Fatty Acid Esters. Originally, it was proposed to the Panel that the polyglyceryl fatty acid esters be included in this re-review. After further consideration, two separate reports were prepared. (The safety assessment of the Polyglyceryl Fatty Acid Esters is scheduled for review at the December meeting.)

Finally, much of the new data included in this safety assessment was found on the European Chemicals Agency (ECHA) website.20-23 Please note that the ECHA website provides summaries of information generated by industry, and it is those summary data that are reported in this safety assessment when ECHA is cited.

CHEMISTRY Definition and Structure

The monoglyceryl monoesters are structurally constituted of the esterification products of one equivalent of glycerin and one equivalent of a fatty acid. These ingredients vary only in the identity of those fatty acids (e.g., variable length, branching, and unsaturation of those acid residues). The definitions and idealized structures of the monoglyceryl monoesters are provided in Table 2.

Figure 1. Glyceryl Pentadecanoate, a monoglyceryl monoester

Physical and Chemical Properties Please refer to the original reports on the previously reviewed monoglyceryl monoesters.

Method of Manufacture Glyceryl Oleate SE The self-emulsifying grade of glyceryl oleate can be formulated by mixing glyceryl oleate with 5% of an anionic surfactant.24

Glyceryl Monoesters – general Industrial monoglycerides can be prepared by the direct esterification of glycerol with a fatty acid, yielding mixtures of mono-, di-, and triglycerides, depending on the molar ratio of the reactants.25

Glyceryl Oleate Glyceryl oleate is manufactured by the partial hydrolysis of corresponding tri- and diglycerides, by esterification of glycerol with oleic acid, or by glycerolysis of common fats and oils.3 The glycerolysis of fats and oils, a transesterification reaction, is a common commercial method for the preparation of monoglycerides.

Natural Occurrence Glyceryl acetate may be a natural component of tobacco or a product of pyrolysis (in tobacco smoke).26

Impurities/Constituents Glyceryl Monoesters – general According to one source, glyceryl monoesters are not pure monoesters, but are mostly mixtures with mono-, di-, and triesters in a ratio of approximately 4:4:2, respectively.25 Another source indicates that the guaranteed purity of commercial and con-ventional monoglyceride (glyceryl monoester) is a minimum of 90%, meaning that impurities account for a maximum of 10%


http://www.cir-safety.org/ingredients

of the composition. The results of impurities analyses of 14 glyceryl monoesters indicated that only one, glyceryl palmitate/ stearate, contained (mono)glycerol diester at a concentration of 1.2%.

Glyceryl Stearate and Glyceryl Stearate SE Glyceryl stearate and glyceryl stearate SE may contain mono-, di-, and triglyceride impurities and fatty acid impurities.1

UV Absorption Glyceryl Ricinoleate Glyceryl ricinoleate absorb UV light, with a maximum absorbance at 270 nm.5

USE Cosmetic

The safety of the cosmetic ingredients included in this assessment is evaluated on the basis of the expected use in cosmetics. The Panel utilizes data received from the U.S. Food and Drug Administration (FDA) and from the cosmetics industry in determining the expected cosmetic use. The data received from the FDA are those collected from manufacturers on the use of individual ingredients in cosmetics by product category in its Voluntary Cosmetic Registration Program (VCRP). Data from the cosmetic industry are submitted in response to a survey of maximum use concentration by product category con-ducted by the Personal Care Products Council (Council).

Based on information from the VCRP and that received from the Council, 25 of the 45 ingredients included in this safety assessment are in use.27-29 Of those, glyceryl stearate has the highest frequency of use; according to the 2015 VCRP data, glyceryl stearate is reported to be used in 5153 formulations, and 4229 of those uses are in leave-on formulations. Glyceryl stearate SE has the next highest frequency of use, with 1420 reported uses27 (Table 4).

The results of the concentration of use survey conducted by the Council in 2014 indicate that for the monoglyceryl mono-esters in this group, glyceryl stearate has the highest maximum use concentration in leave-on formulations (17% in a deodor-ant), and glyceryl ricinoleate has the second highest maximum use concentration in leave-on formulations (15.2% in lip-stick).28,29 Overall, glyceryl rosinate is reported to have the greatest maximum reported used concentration, i.e., 96% in a depilatory (Table 4).

Most of the in-use ingredients have been reviewed previously by the Panel. For the majority of these ingredients, the frequency of use has increased but the concentration of use has remained the same or decreased. For example, in 1976 glyceryl stearate was reported to be used in 1371 cosmetic formulations at concentrations up to 50%;1 currently, it is reported to be used in 5153 formulations at a maximum concentration of 18.9%. Additionally, for those ingredients that now have a higher concentration of use than what was reported historically, that increase has been relatively small. However, glyceryl rosinate and glyceryl hydrogenated rosinate are exceptions. The maximum concentration of use of glyceryl rosinate has increased from 12% in 19996 to 96% in 2014. The primary reason for this increase is that glyceryl rosinate is now reported to be used at maximum concentrations of 72-96% in depilatories; yet, the next greatest concentration of use of glyceryl rosinate is 8% in mascara, which is a decrease from the 12% concentration of use in mascara reported in 1999. Glyceryl hydrogen-ated rosinate was not reported to be used in 1998, but now has 29 uses, with maximum use concentrations of 10% in leave-on products (lipstick) and 76.8% in rinse-off products (depilatories).

The 20 monoglyceryl monoesters not currently reported to be in use in use, according to the VCRP and industry survey, are listed in Table 5.

Several of the monoglyceryl monoesters are used in products that can be ingested, used near the eye, or come in contact with mucous membranes. Glyceryl ricinoleate is used at 11.6% in eyeliner and at 15.2% in lipstick (possible ingestion and mucous membrane exposure). (In the 2007 review of glyceryl ricinoleate, the use in lipstick was known, but a concentration of use was not reported.5)

Additionally, some of the monoglyceryl monoesters are used in cosmetic sprays and could possibly be inhaled; for example, glyceryl stearate is reported to be used at a maximum concentration of 14% in perfumes. In practice, 95% to 99% of the droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters >10 µm, with propellant sprays yielding a greater fraction of droplets/particles <10 µm compared with pump sprays.30,31 Therefore, most droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and thoracic regions of the respiratory tract and would not be respirable (i.e., they would not enter the lungs) to any appreciable amount.32,33 Some of the ingredi-ents are used in spray deodorants; for example, glyceryl cocoate is used at a maximum concentration of 2% in a pump spray deodorant formulation. There is some evidence indicating that deodorant spray products can release substantially larger fractions of particulates having aerodynamic equivalent diameters in the range considered to be respirable.32 However, the information is not sufficient to determine whether significantly greater lung exposures result from the use of deodorant sprays, compared to other cosmetic sprays.

All of the monoglyceryl monoesters named in the report are listed in the European Union inventory of cosmetic ingredients.34


Non-Cosmetic According to the FDA, many of the monoglyceryl monoesters are direct food substances affirmed as generally recognized as safe (GRAS) for human and/or animal use, are permitted as direct food additives, or are permitted as indirect food additives. The food additive status of the monoglyceryl monoesters is provided in Table 6.

Glyceryl Acetate Glyceryl acetate is used as a gelatinizing agent for explosives, in leather tanning, and as a solvent for basic dyes.26 In may be an additive for one or more types of tobacco products.

Glyceryl Monoesters - general Glyceryl monoesters have been approved by the FDA for use as direct or indirect food additives. 25

Glyceryl Oleate Glyceryl oleate has numerous applications in the pharmaceutical field.24 Examples of these applications include emulsifier, solubilizer, absorption enhancer, oral drug delivery system, and vaginal drug delivery system.

Monoglycerides of edible fats or oils are considered GRAS and indirect food additives for human consumption by the FDA.3 Glyceryl oleate can be used as a prior-sanctioned food ingredient and as a direct and indirect food additive. The pharma-ceutical industry uses glyceryl oleate as an inert carrier compound and to enhance intestinal drug absorption.

Glyceryl Ricinoleate Glyceryl ricinoleate is listed by the FDA as an inactive ingredient in drug preparations.4

Glyceryl Stearate Glyceryl stearate is widely used in foods as a surfactant, emulsifier, and thickener. Glyceryl stearate is an antistalant and dough conditioner in breads and is also used in pharmaceutical bases. Glyceryl stearate has been granted regulatory status (by the FDA) as GRAS ingredient, an indirect food additive, a direct food additive, and as an over-the counter (OTC) substance1.

TOXICOKINETICS Absorption, Distribution, Metabolism, and Excretion

Oral Glyceryl Rosinate Four groups of Fischer 344 rats were orally administered glycerol ester of wood rosin; the labeled compound was prepared using 1,3-[14C] glycerol.23 One group of 8 females was fed a diet containing 14,000 ppm unlabeled ester for 18 hours, and two groups of 8 males were fed a diet containing 14,000 ppm unlabeled ester for 20 hours or 10 days, respectively; 5 rats from each of the 3 group was administered a single dose of 200 mg/kg bw [14C]glycerol ester of wood rosin by gavage after completion of dietary administration. The animals were then placed in metabolism cages, and expired CO2, urine, and feces were collected from each animal at 0-12 h, 12-24 h, and subsequent 24-h intervals through 120 h after dosing. The animals were then killed.

Less than 1% (males) to 2% (females) of the administered radioactivity was recovered in either expired CO2, urine or the cage rinses with 120 h of administration; the majority of the radioactivity was excreted in the feces. Small traces of radio-activity were detectable in the carcasses; this trace material was most likely residual radioactivity in the gastrointestinal tract. No metabolites were specifically identified; however, analysis of fecal extracts following dosing indicate that little hydrolysis occurred, and results were similar with 1-day and 10-day dietary administration.

In the fourth group, jugular vein cannulas were implanted in 9 male rats and the following day, 6 of these rats were also implanted with biliary cannulas. The 6 rats implanted with 2 cannulas were then dosed by gavage with 200 mg/kg bw [14C]glycerol ester of wood rosin. Excreted bile was collected continuously, and samples were obtained at 4, 8, 12, and 24 h after dosing, and blood samples were obtained from the jugular cannula at the same time intervals. The animals were killed 24 h after dosing. Low levels of radioactivity were absorbed by the rats following dosing, and the radioactive species excreted in bile appeared to be a hydrolyzed product of the administered test substance; no intact test substance was present. Radioactivity was excreted in bile within 4 h after dosing and was detectable in all samples collected for 24 h post dose. The total amount of radioactivity excreted in bile during the 24-h collection period ranged from 1.6-2.9% of the dose. Radioacti-vity content in the liver only accounted for 0.1-0.2% of the administered dose.

Glyceryl Monoesters – general Glyceryl monoesters (monoglycerides) are metabolized to free fatty acids and glycerol, both of which are available for the resynthesis of triglycerides.25

Glyceryl Ricinoleate Upon ingestion, glyceryl ricinoleate is absorbed into the intestinal mucosa.4


Penetration Enhancement Monoglyceryl monoesters can act as penetration enhancers. Several studies demonstrating this behavior are summarized in Table 7.35-39

Glyceryl Laurate Glyceryl Laurate enhanced the penetration of drugs through cadaverous skin and hairless rat skin in vitro.25.

TOXICOLOGICAL STUDIES Single Dose (Acute) Toxicity

Single dose (acute) toxicity studies are summarized in Table 8.

The dermal LD50 of glyceryl rosinate is >10 g/kg bw in rabbits in a 24-h patch test.23 In oral studies, the LD50 of glyceryl behenate and glyceryl hydrogenated rosin is >2 g/kg, of glyceryl stearate is >5 g/kg, and of glyceryl rosinate is >10 g/kg.20,21,23

Dermal Glyceryl Citrate/Lactate/Linoleate/Oleate In an acute dermal toxicity study in rats, 2000 mg/kg glyceryl citrate/lactate/linoleate/oleate did not induce toxicity in rats that received a single oral dose of 2000 mg/kg.25

Oral Glyceryl Citrate/Lactate/Linoleate/Oleate Glyceryl citrate/lactate/linoleate/oleate did not induce toxicity in rats that received a single oral dose of 2000 mg/kg.25

Glyceryl Isostearate Glyceryl isostearate did not induce toxicity in rats that received a single oral dose of 2000 mg/kg.25

Glyceryl Laurate An LD50 of >20,000 mg/kg was reported for rats dosed orally with glyceryl laurate.25

Glyceryl Oleate Oral administration of a single 13 ml/kg dose of a sunscreen formulation containing 5% glyceryl oleate to rats produced no signs of toxicity and no lethality.3

Glyceryl Ricinoleate Acute oral toxicity tests indicated that glyceryl ricinoleate has an LD50 greater than 25.0 ml/kg in mice and that products containing 5.6% glyceryl ricinoleate were not toxic when ingested.4

Glyceryl Rosinate Undiluted, purified ester gum-2-octyldodecyl myristate (contains 50% glyceryl rosinate and 50% octyldodecyl myristate) was not toxic (LD50 > 5 g/kg) when administered orally to fasted Wistar albino rats (five males, five females).25 None of the animals died.

Glyceryl Stearate and Glyceryl Stearate SE In acute oral toxicity studies in rats, glyceryl stearate an glyceryl stearate/SE were nontoxic or mildly toxic.1

Repeated Dose Toxicity Repeated dose toxicity studies are summarized in Table 9.

In a 90-day dietary study, the no-observable adverse effect level (NOAEL) for glyceryl hydrogenated rosinate in rats was 10,000 ppm. For glyceryl rosinate, the NOAEL for rats was 1% in one 90-day study, and 2500 mg/ kg bw/day in another. In a 28-day study of glycerides, C8-18 and C18-unsatd. mono- and di-, acetates in rats, the NOAEL was 1000 mg/kg bw/day.20,23

Intravaginal dosing with 5% glyceryl oleate for 6 mos in monkeys did not induce vaginal inflammation or mucosal lesions in cervical vaginal tissues.40

Animal Dermal Glyceryl Stearate In subchronic and chronic dermal toxicity tests, 4-5% glyceryl stearate was nontoxic to rabbits but did cause moderate irritation (slight to moderate erythema, edema, atonia, desquamation, and/or fissuring).1


Oral Glyceryl Laurate No test substance-related gross or microscopic changes were observed in albino rats fed a mixture of mono-, di-, and triglycerides containing 40% to 45% glyceryl laurate for two.25

years.

Glyceryl Stearate In chronic studies, 15-25% glyceryl stearate in the diet of rats for three consecutive generations had no adverse effects. 1 Rats fed a diet containing 25% glyceryl stearate for two years developed renal calcifications.

Inhalation Glyceryl Laurate A no-effect level of 280 mg/m3 was reported for glyceryl laurate in a short-term inhalation toxicity study involving rats.25 Rats were subjected to 14 1-hour exposures during a 3-week period. Neither gross nor microscopic lesions were noted in rats fed 25% Glyceryl laurate in another short-term (10 weeks) study.

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Glyceryl Oleate A reproduction/developmental toxicity screening test was conducted in male and female Sprague-Dawley rats for glyceryl oleate.21 Both males and females were dosed by gavage with 0, 100, 300, or 1000 mg/kg bw/day glyceryl oleate in corn oil once daily for 14 days prior to mating; the males were dosed for an additional 28 days, and dosing of the females continued until day 4 of lactation. The groups were comprised of 12 females for the control and 3 test groups, 7 males in the control and high dose groups, and 12 males in the low- and mid-dose groups. A satellite group of 5 males and 5 females were dosed for 42 days, with a 14-day post-dosing observation period. The NOAELs for systemic toxicity (males and females), fertility (males and females), and development (F1 generation) were 1000 mg/kg bw/day. No effects related to the administration of the test-article were observed in parental animals or offspring.

For Read-Across In the 28-day oral toxicity study with 0, 100, 300 and 1000 mg/kg/day glycerides, C8-18 and C18-unsatd. mono- and di-, acetates in polyethylene glycol described in Table 9 (Repeated Dose Toxicity Studies), an additional 10 female Wistar Han rats were included in each group to assess reproduction and developmental toxicity.20 After a minimum of 14 days of dosing, females of the reproduction study group were cohabitated with a male from the same treatment group. The test females were dosed for a total of 41-49 days, i.e. during those 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation. No treatment-related effects were observed, and the NOAEL for parental fertility was 1000 mg/kg bw/day.

Glyceryl Hydrogenated Rosinate and Glyceryl Rosinate Following the administration of hexane extracts of Pinus ponderosa needles to mice by stomach tube, increased embryonic resorptions were observed.25 Glyceryl rosinate and glyceryl hydrogenated rosinate are esters of glycerin and acids derived from rosin, and rosin is obtained from trees of various species of Pinus.

GENOTOXICITY Genotoxicity studies are summarized in Table 10.

Glyceryl acetate was not mutagenic in an Ames test (≤10,000 µg/plate) or chromosomal aberration assay (≤5000 µg/plate) with or without metabolic activation; in a sister chromatid exchange assay, it was not genotoxic with metabolic activation, but without activation, a dose-dependent increase was observed in 2 trials, and a doubling of sister chromatid exchanges (SCEs) was produced with 5000 µg/ml.41,42 Glyceryl laurate was not mutagenic in an Ames test (≤5000 µg/plate), and glyceryl rosinate was not mutagenic in an Ames test (≤500 µg/plate), mammalian chromosome assay (≤507 µg/ml), or unscheduled DNA synthesis test (≤102 µg/ml).22,43 Glycerides, C16-18 and C18-hydroxy mono- and di- (up to 10,000 mg/kg bw) was not genotoxic in a mouse micronucleus test.20

In Vitro Glyceryl Citrate/Lactate/Linoleate/Oleate In Ames plate incorporation and preincubation mutagenicity tests, glyceryl citrate!lactate!linoleate/oleate was not mutagenic (with or without metabolic activation) to the following Salmonella typhimurium strains: TA 98, TA 100, TA 1535, and TA 1537.25


Glyceryl Hydrogenated Rosinate and Glyceryl Rosinate In studies on the mutagenicity of resin acids, only neoabietic acid (component of rosin) was mutagenic in the Ames/ Salmonella assay. glyceryl rosin ate and glyceryl hydrogenated rosinate are esters of glycerin and acids derived from rosin, which is composed of diterpene resin acids.25

CARCINOGENICITY Oral Glyceryl Oleate Glyceryl oleate administration was associated with development of a few brain tumors (3 tumors in 63 mice) in a two-generation study in mice of the T.M. strain whose feed was supplemented with 50-100 mg/mouse per day glyceryl oleate.3 Digestive tract tumors were found in T.M. strain mice fed 200 mg/mouse per day glyceryl oleate (feed supplement) for four-seven generations and were considered due to free fatty acid impurities. The Expert Panel found the results of these studies equivocal.

Glyceryl Ricinoleate Glyceryl ricinoleate was not a tumor promoter in a study involving groups of ten mice.5 However, the test substance induced slight epidermal hyperplasia in groups of three mice following the application of each to a small area of skin in the interscapular region.

Glyceryl Stearate Glyceryl stearate, fed to mice in doses of 50-100 mg/day or 1.5% in the diet until they died, did not induce significant brain or gastric tumor formation, respectively. Five percent glyceryl stearate did not promote the carcinogenicity of 9,10-dimethyl-benz(a)anthracene (DMBA) in mouse skin.1

IRRITATION AND SENSITIZATION Dermal Irritation/Sensitization

Dermal irritation and sensitization studies are summarized in Table 11.

Undiluted glyceryl behenate, and glyceryl hydrogenated rosinate, and glyceryl rosinate were not irritating to rabbit skin. Glyceryl hydrogenated rosinate (challenge at up to 50%), glyceryl rosinate (challenge at 100%), and glyceride, C16-18 and C18 mono- and dihydroxy (25% at challenge) were not sensitizers in guinea pigs.20,21,23

In clinical testing, 5% glyceryl stearate was not irritating and glyceryl behenate (applied neat), glyceryl hydrogenated rosinate, and glyceryl rosinate were not sensitizers in human repeated insult patch tests (HRIPTs).21,23,44

Non-Human Glyceryl Citrate/Lactate/Linoleate/Oleate Neither erythema nor edema was observed in rabbits after semi-occlusive patches containing heated glyceryl citrate/lac-tate/linoleate/oleate (single application) were applied to intact skin. In another study, glyceryl citrate/lactate/linoleate/oleate (single application) induced clearly circumscribed erythema and very mild edema when applied to intact skin of rabbits.25 All reactions had cleared by day 10 post application.

The sensitization potential of glyceryl citrate/lactate/linoleate/oleate in 20 guinea pigs was evaluated using the Buehler method.25 Following the dermal application of undiluted test substance during induction and challenge phases, no evidence of irritation or sensitization was observed.

Glyceryl Isostearate Overall, glyceryl isostearate was classified as nonirritating to the skin of rabbits in a study in which single, semi-occlusive patch applications were made to intact skin.25 The most severe reaction (moderate irritation) did not clear until day 5 post removal. Glyceryl isostearate was also classified as nonirritating to the skin of rabbits in another study in which single occlusive patch applications were made to intact and abraded skin sites.

Glyceryl isostearate was also evaluated in the maximization test.25 After induction, ten guinea pigs were challenged with 50% glyceryl isostearate in polyethylene glycol (PEG) and microcrystalline cellulose (MCC). Two additional challenges were also conducted. The first challenge yielded one and two positive reactions (all slight reactions) at 24 and 48 h, respectively. These results were confirmed by reactions observed after the third challenge.

Glyceryl Laurate Undiluted glyceryl laurate induced minor erythema and edema when applied (occlusive patches, single application) to intact skin of rabbits.25 In another study, single occlusive patch applications of 20% glyceryl laurate emulsion to abraded and ntact skin caused moderate skin irritation in rabbits.


The skin sensitization potential of glyceryl laurate was evaluated in the maximization test.25 Guinea pigs were subjected to four sensitizing injections of 2% glyceryl laurate and then challenged with intradermal injections of 0.8% glyceryl laurate and topical applications of 25% glyceryl laurate. No positive reactions were observed. In another maximization test, skin sensitization was induced in 2 of I 0 guinea pigs challenged with a 10% dilution of 20% glyceryl laurate emulsion. When a second challenge was initiated 7 days after the first, positive reactions were observed in five animals. Positive reactions were also observed in four animals challenged with a 5% dilution of 20% glyceryl laurate emulsion. Because positive reactions were also noted in the control group after the first and second challenge, the results were attributed to skin irritation (but not sensitization) effects of the test substance.

Glyceryl Oleate Undiluted and 50% in corn oil concentrations of glyceryl oleate used in dermal irritation studies with rabbits were found to be minimally irritating.3 A volume of 0.5 ml of a sunscreen formulation containing 5% glyceryl oleate produced erythema and slight edema in rabbits. Daily applications of 2.0 ml/kg of a 25.0% corn oil solution of a formulation containing glyceryl oleate for 20 days produced severe dermal irritation in rabbits.3 In another 4-week dermal toxicity/phototoxicity study, product formulations containing varying concentrations of two sunscreen ingredients produced slight, reversible dermal irritation. Each sunscreen ingredient contained 5% glyceryl oleate.

Glyceryl Ricinoleate Glyceryl ricinoleate, when evaluated by a Draize skin test, was a mild irritant to rabbits.4 In a primary skin irritation test in rabbits, glyceryl ricinoleate was classified as a nonirritant. When rabbits were tested with products containing 5.6% glyceryl ricinoleate in a single-insult occlusive patch test, the products had either no (four of five tests) or mild (one of five tests) irritation potentials.

Glyceryl Rosinate A primary irritation index (PII) of 3.40 (potential for severe irritation-warning label may be considered) was reported in an occlusive patch test evaluating the skin irritation potential of undiluted, purified ester gum-2-octyldodecyl myristate (contains 50% glyceryl rosinate and 50% octyldodecyl myristate) in rabbits.25 Follicular hyperkeratosis (comedone formation) was not observed in another study in which the same undiluted test substance was applied to the ears of rabbits.

Glyceryl Stearate and Glyceryl Stearate SE Glyceryl stearate and glyceryl stearate/SE at concentrations of up to 100% were reported to be mildly irritating or non-irritating to the skin of rabbits.1 In seven guinea pig sensitization studies, it was concluded that neither glyceryl stearate nor glyceryl stearate/SE was capable of inducing sensitization.

Human Glyceryl Caprylate Glyceryl caprylate (15%) did not induce skin irritation or sensitization in a repeated insult patch test (RIPT) involving 63 healthy subjects, 58 of whom completed the study.25

Glyceryl Hydrogenated Rosinate Neither skin irritation nor sensitization was observed in any of the 51 subjects patch tested (semi-occlusive patches) with a material consisting of 20% hydrogenated purified ester gum-2-octyldodecyl myristate and 80% white petrolatum·(a.k.a. hydrogenated PEGMOD [20]).25 (Because hydrogenated purified ester gum-2-octyldodecyl myristate is a trade mixture consisting of 50% hydrogenated glyceryl rosinate and 50% octyldodecyl myristate, the effective concentration of hydrogenated glyceryl rosinate in the test material is 1 0%.) The subjects were challenged at a new test site, but not at the original site.

Glyceryl Laurate Glyceryl laurate was tested at a concentration of 50% w/v, in liquid paraffin, in a RIPT (Finn chambers) involving 91 healthy human subjects.25 Glyceryl laurate induced mild, erythematous reactions during induction in most of the subjects and questionable reactions in seven subjects during the challenge phase. Reactions ranged from mild to moderate erythema (score = 2) during induction and challenge phases.

The skin irritation and sensitization potential of glyceryl laurate was evaluated in a second RIPT (Finn chambers) using 107 healthy subjects, 93 of whom completed the study.25 Glyceryl laurate was tested at a concentration of 25% in liquid paraffin oil. Glycery1 laurate induced moderate erythema (score= 2) in eight subjects during induction and in one subject during the challenge phase. It was considered a sensitizer.


Glyceryl Linoleate Glyceryl laurate was tested at a concentration of 50% w/v, in liquid paraffin, in a RIPT (Finn chambers) involving 91 healthy human subjects.25 Glyceryl Linoleate did not induce skin irritation or sensitization in the 74 subjects who completed the study.

Glyceryl Myristate The skin irritation and sensitization potential of glyceryl myristate was evaluated in a RIPT (Finn chambers) using 107 healthy subjects, 93 of whom completed the study.25 It was tested at a concentration of 50% in paraffin oil. Glyceryl myristate did not induce irritation or sensitization.

Glyceryl Oleate Two aqueous glyceryl oleate preparations (15% and 30% concentrations) and a fragrance preparation containing 19.0% glyceryl oleate were negative for cutaneous irritation when tested on human skin using single insult occlusive patch tests.3 Two sunscreen formulations containing 5% glyceryl oleate were considered mild compounds and caused no irritation in a cumulative occlusive patch test using human subjects.3 No signs of irritation or sensitization were observed in humans after repeated insult patch testing of a 15% aqueous glyceryl oleate preparation and a sunscreen formulation containing 5% glyceryl oleate.3 A few subjects involved in simultaneous photoallergy and phototoxicity tests had slight, transient erythematous responses. No positive reactions were observed at any irradiated site during induction and challenge phases of the photoallergy test. The skin irritation and sensitization potential of glycery1 oleate was evaluated in a RIPT (Finn chambers) using 107 healthy subjects, 93 of whom completed the study.25 Glyceryl oleate were tested at a concentration of 50% in paraffin oil. Glyceryl oleate did not induce irritation or sensitization.

Glyceryl Rosinate Skin irritation was not observed in 12 healthy volunteers patch tested (occlusive patches) with a lipstick containing 1.0% glyceryl rosinate.25 Neither skin irritation nor sensitization was observed in 78 healthy volunteers patch tested (occlusive patches) with the same product in a repeated insult patch test.

The contact sensitization potential of three product formulations containing glyceryl rosinate was evaluated in three maximization assays (healthy human subjects), respectively.25 Results were negative for the following three study groups: foundation containing 4.0% glyceryl rosinate (25 subjects), blush containing 2.0% glyceryl rosinate (27 subjects), and lip gloss containing 2.0% glyceryl rosinate (27 subjects).

Skin irritation and sensitization were observed in one of 49 subjects patch tested (RIPT, semi-occlusive patches) with a material consisting of 20% purified ester gum-2-octyldodecyl myristate and 80% white petrolatum (a.k.a. PEGMODWP-20).25 (Because purified ester gum-2-octyldodecyl myristate is a trade mixture consisting of 50% glyceryl rosinate and 50% octyldodecyl myristate, the effective concentration of glyceryl rosinate in the test material is 1 0%.) The challenge reaction was observed at the original test site, but not at the new site. It was concluded that the positive reaction observed was unique to that individual.

Glyceryl Stearate Single and repeated insult patch tests used to evaluate human skin irritation and sensitization potential of glyceryl stearate and glyceryl stearate/SE showed both ingredients to be nonsensitizing and nonirritating.1

Allergenicity Non-Human Glyceryl Rosinate The reaction of rosin with glycerol to form two esterification products (glyceryl triabietate [GTA] and glycerol esterified tall oil rosin [TORG]), in effect, reduced the allergenicity of rosin.25 GTA results from the esterification of glycerol with abietic acid, the major component of rosin.25 The incidence of positive challenge reactions in 15 guinea pigs tested was as follows: 1 (8.3% GTA), 2 (10% TORG), 3 (0.93% and 2.8% GTA), and 9 (20% gum rosin). Glyceryl diabietate and glyceryl mono-abietate induced either the same incidence or a higher incidence of sensitization in other experiments (similar test groups) in the same study.

Human Glyceryl Ricinoleate In human single-insult occlusive patch tests, no indication of skin irritation potential was observed in the two products tested (each contained 5.6% glyceryl ricinoleate).4


Glyceryl Rosinate Data on 12 patients suspected of having gum rosin allergy indicated that sensitization to Portuguese gum rosin exhibited a dose-response relationship (0.001% to 20%).25 In the same study, the incidence of positive reactions to Portuguese gum rosin in a second group of 12 patients with gum rosin allergy was summarized as follows: 0.001% gum rosin (0 to 1 patient), 0.01% gum rosin (2 to 3 patients), 0.1% gum rosin (8 patients), 1% gum rosin (12 patients), and 10% gum rosin (10 to 12 patients). These data were based on patch tests with serial dilutions of Portuguese gum rosin in petrolatum.

The esterification of rosin with glycerol, in effect, reduced the allergenicity of rosin in dermatitis patients.25 Five of eight patients had positive reactions to 10% tall oil rosin in petrolatum, whereas four of eight patients had positive reactions to 20% glycerol-esterified tall oil rosin in petrolatum. Additionally, seven of eight patients had positive reactions to 5% Portuguese gum rosin in petrolatum and three of eight patients had positive reactions to 20% glycerol-esterified gum rosin in petrolatum.

Glyceryl-1-monoabietate was identified as a contact allergen in another study evaluating the allergenicity of rosin and its esterification products.25 Abietic acid (esterified to form glyceryl- 1-monoabietate) is a main component of rosin, and, furthermore, clinical data indicate that it is easily oxidized to form contact allergens (e.g., 15~hydroperoxyabietic acid and its methyl ester). It is also important to note that oxidation products of abietic acid and dehydroabietic acid (also a main component of rosin) that can be formed during storage have been found to be allergenic.

Phototoxicity Glyceryl Isostearate No evidence of significant cutaneous reactions, with or without UV irradiation, was found when the phototoxicity and photoallergenicity potential of glyceryl isostearate was evaluated using 20 guinea pigs.25

Glyceryl Rosinate Phototoxicity was not induced in a group of 10 healthy volunteers tested with a lipstick containing 1.0% glyceryl rosinate. Patches were not applied to test sites.25 Similarly, photoallergenicity was not induced in a group of 26 healthy volunteers patch tested (occlusive patches) with the same product in a repeat insult patch test.

Glyceryl Stearate Products containing 2% glyceryl stearate were non-phototoxic and non-photoallergic.1

Ocular Irritation Ocular irritation studies are summarized in Table 12.

Undiluted glyceryl behenate and glyceryl palmitate/stearate were non-irritating to rabbit eyes, and undiluted glyceryl rosinate was slight irritating.20,21,23

Glyceryl Citrate/Lactate/Linoleate/Oleate Glyceryl citrate/lactate/linoleate/oleate was not classified as ocular irritants in rabbits.25

Glyceryl Isostearate Glyceryl isostearate was not classified as ocular irritants in rabbits.25

Glyceryl Laurate Glyceryl laurate was not classified as ocular irritants in rabbits.25

Glyceryl Oleate Minimal to moderate eye irritation was produced by undiluted glyceryl oleate, 50% glyceryl oleate in corn oil, and a fragrance preparation containing 19.0% glyceryl oleate when administered to rabbits.3 A formulation containing 5% glyceryl oleate administered at a 0.1 ml dose to rabbit eyes induced slight conjunctivitis.

Glyceryl Ricinoleate Glyceryl ricinoleate was nonirritating to rabbit eyes in a primary eye irritation test, and in a Draize test, it was mildly irritating to rabbit eyes from which it was not rinsed but nonirritating to rabbit eyes from which it had been rinsed 2 and 4 sec after instillation.4 Various products containing glyceryl ricinoleate were tested for irritation potential in rabbit eyes. Of eight tests, two products demonstrated no irritation potential, five products had a minimal irritation potential, and one product had a mild irritation potential.

Glyceryl Rosinate Undiluted, purified ester gum-2-octyldodecyl myristate (contains 50% glyceryl rosinate and 50% octyldodecyl myristate) was not irritating to the eyes of rabbits.25


Glyceryl Stearate In primary eye irritation studies, glyceryl stearate and glyceryl stearate/SE at concentrations up to 100% were mildly irritating or non-irritating when instilled in the eyes of rabbits.1

Case Reports Case reports of reactions to use of formulations containing several of the monoglyceryl monoesters are described in Table 13.45-49

Glyceryl Isostearate Two case reports indicated skin reactions to two cosmetic products containing glyceryl isostearate, as well as positive patch test reactions to this ingredient.25

SUMMARY In 1982, the Panel concluded that glyceryl stearate and glyceryl stearate SE are safe for topical application to humans. Since that time, the Panel has issued final reports on other monoglyceryl monoesters, finding them all safe as used in cosmetic products; an additional 8 monoglyceryl monoesters that are cosmetic ingredients and have not been reviewed by the Panel have also been identified. This safety assessment is a compilation of these 45 monoglyceryl monoesters, and these ingredients are similar because they are all constituted of the esterification products of glycerin and fatty acids. Most of the monoglyceryl monoesters included in this safety assessment are reported to function as skin conditioning agents.

Twenty-five of the 45 ingredients included in this safety assessment are in use, and glyceryl stearate has the highest frequency of use, 5153 formulations. Glyceryl stearate also has the highest maximum use concentration in leave-on formulations (17% in a deodorant), and glyceryl ricinoleate has the second highest maximum use concentration in leave-on formulations (15.2% in lipstick); overall, glyceryl rosinate is reported to have the greatest maximum reported used concentration (96% in a depilatory). Most of the in-use ingredients have been reviewed previously by the Panel; for the majority of these ingredients, the frequency of use has increased but the concentration of use has remained the same or decreased.

According to the FDA, many of the monoglyceryl monoesters are direct food substances affirmed as GRAS for human and/or animal use, are permitted as direct food additives, or are permitted as indirect food additives. Monoglyceryl monoesters can act as penetration enhancers.

In rats fed a diet containing radiolabeled glycerol ester of wood rosin, most of the radioactivity was excreted in the feces, primarily unchanged; results were similar with 1-day and 10-day dietary administration. In rats dosed by gavage, low levels of radioactivity were absorbed by the rats following dosing, and the radioactive species excreted in bile appeared to be a hydrolyzed product of the administered test substance; no intact test substance was present. Radioactivity was excreted in bile within 4 h after dosing and was detectable in all samples collected for 24 h post dose. The total amount of radioactivity excreted in bile during the 24-h collection period ranged from 1.6-2.9% of the dose.

In a 24-h patch test, the dermal LD50s of glyceryl rosinate and of glycerides, C16-18 and C18-hydroxy mono- and di-are >10 and >2 g/kg bw in rabbits, respectively. In oral studies, the LD50 of glyceryl behenate and glyceryl hydrogenated rosin is >2 g/kg, of glyceryl stearate is >5 g/kg, and of glyceryl rosinate is >10 g/kg. In a 90-day dietary study, NOAEL for glyceryl hydrogenated rosinate in rats was 10,000 ppm. For glyceryl rosinate, the NOAEL for rats was 1% in one 90 day study, and 2500 mg/ kg bw/day in another. In a 28-day study of glycerides, C8-18 and C18-unsatd. mono- and di-, acetates in rats, the NOAEL was 1000 mg/kg bw/day.

Intravaginal dosing with 5% glyceryl oleate for 6 mos in monkeys did not induce vaginal inflammation or mucosal lesions in cervical vaginal tissues.

Glyceryl oleate was not a reproductive or developmental toxin in rats. The NOAELs for systemic toxicity (males and females), fertility (males and females), and development (F1 generation) were 1000 mg/kg bw/day. No effects related to the administration of the test-article were observed in parental animals or offspring. In a reproductive and developmental toxicity study in which rats were dosed with 0, 100, 300 and 1000 mg/kg/day glycerides, C8-18 and C18-unsatd. mono- and di-, acetates in polyethylene glycol, no treatment-related effects were observed, and the NOAEL for parental fertility was 1000 mg/kg bw/day.

Glyceryl acetate was not mutagenic in an Ames test (≤10,000 µg/plate) or chromosomal aberration assay (≤5000 µg/plate) with or without metabolic activation; in a sister chromatid exchange assay, it was not genotoxic with metabolic activation, but without activation, a dose-dependent increase was observed in 2 trials, and a doubling of sister chromatid exchanges (SCEs) was produced with 5000 µg/ml. Glyceryl laurate was not mutagenic in an Ames test (≤5000 µg/plate), and glyceryl rosinate was not mutagenic in an Ames test (≤500 µg/plate), mammalian chromosome assay (≤507 µg/ml), or unscheduled DNA synthesis test (≤102 µg/ml). Glycerides, C16-18 and C18-hydroxy mono- and di- (up to 10,000 mg/kg bw) was not genotoxic in a mouse micronucleus test


Undiluted glyceryl behenate, and glyceryl hydrogenated rosinate, and glyceryl rosinate were not irritating to rabbit skin. Glyceryl hydrogenated rosinate (challenge at up to 50%), glyceryl rosinate (challenge at 100%), and glyceride, C16-18 and C18 mono- and dihydroxy (25% at challenge) were not sensitizers in guinea pigs. In clinical testing, 5% glyceryl stearate was not irritating and glyceryl behenate (applied neat), glyceryl hydrogenated rosinate, and glyceryl rosinate were not sensitizers in HRIPTs. Case reports of reactions to use of formulations containing several of the monoglyceryl monoesters have been described.

Undiluted glyceryl behenate and glyceryl palmitate/stearate were non-irritating to rabbit eyes, and undiluted glyceryl rosinate was slight irritating.


TABLES Table 1. Monoglyceryl Monoesters Glyceryl Acetate* Glyceryl Adipate Glyceryl Alginate Glyceryl Arachidate Glyceryl Behenate Glyceryl Caprate Glyceryl Caprylate Glyceryl Caprylate/Caprate Glyceryl Citrate/Lactate/Linoleate/Oleate Glyceryl Cocoate Glyceryl Cocoate/Citrate/Lactate* Glyceryl Erucate Glyceryl Ethylhexanoate* Glyceryl Ethylhexanoate/Stearate/Adipate* Glyceryl Heptanoate* Glyceryl Hydrogenated Rapeseedate* Glyceryl Hydrogenated Rosinate Glyceryl Hydrogenated Soyate Glyceryl Hydroxystearate Glyceryl Isopalmitate Glyceryl Isostearate Glyceryl Isotridecanoate/Stearate/ Adipate Glyceryl Lanolate

Glyceryl Laurate Glyceryl Laurate SE Glyceryl Laurate/Oleate Glyceryl Linoleate Glyceryl Linolenate Glyceryl Montanate Glyceryl Oleate Glyceryl Oleate SE Glyceryl Oleate/Elaidate Glyceryl Olivate* Glyceryl Palmitate Glyceryl Palmitate/Stearate Glyceryl Palmitoleate Glyceryl Pentadecanoate Glyceryl Ricinoleate Glyceryl Ricinoleate SE Glyceryl Rosinate Glyceryl Stearate Glyceryl Stearate SE Glyceryl Stearate/Malate* Glyceryl Tallowate Glyceryl Undecylenate

*not previously reviewed by CIR

Table 2. Definitions, idealized structures, and functions of the ingredients in this safety assessment. (2; CIR Staff)

Ingredient CAS No. Definition & Structure Function(s) Glyceryl Acetate 26446-35-5

the ester of acetic acid and glycerin

skin conditioning agent - misc

Glyceryl Adipate 26699-71-8

the ester of glycerin and adipic acid that conforms to the formula:

skin conditioning agent - emollient

Glyceryl Alginate the ester of glycerin and alginic acid (Alginic acid is the carbohydrate obtained by the alkaline extraction of various species of brown seaweed, Phaeophyceae.)

wherein RC(O)- represents the residue of alginic acid

skin conditioning agent - emollient; viscosity increasing agent – aq.

Glyceryl Arachidate 30208-87-8 50906-68-8

the monoester of glycerin and arachidic acid. It conforms generally to the formula

skin-conditioning agent - emollient; surfactant – emulsify-ing agent; viscosity in-creasing agent –non-aq



Ingredient CAS No. Definition & Structure Function(s) Glyceryl Behenate 6916-74-1 77538-19-3 30233-64-8

the monoester of glycerin and behenic acid. It conforms generally to the formula

skin-conditioning agent - emollient; surfactant – emulsify-ing agent

Glyceryl Caprate 11139-88-1 26402-22-2

the monoester of glycerin and capric acid. It conforms to the formula


Glyceryl Caprylate 26402-26-6

the monoester of glycerin and caprylic acid. It conforms to the formula


Glyceryl Caprylate/Caprate a monoester of glycerin esterified with a mixture of caprylic and capric acids.

wherein RC(O)- represents the residue of caprylic or capric acid


Glyceryl Citrate/Lactate/Linoleate/Oleate

glycerin esterified with a blend of citric, lactic, linoleic and oleic acids

wherein RC(O)- represents the residue of citric, lactic, linoleic, or oleic acid

skin-conditioning agent - emollient

Glyceryl Cocoate 61789-05-7

the monoester of glycerin and coconut fatty acids. It conforms generally to the formula:

where RC(O)- represents the fatty acids derived from coconut oil


Glyceryl Cocoate/Citrate/Lactate glycerin esterified with a blend of coconut, citric and lactic acids

wherein RC(O)- represents the residue of coconut, citric, or lactic acid


Glyceryl Erucate 28063-42-5

the monoester of glycerin and erucic acid. It conforms generally to the formula


Glyceryl Ethylhexanoate the ester of glycerin and ethylhexanoic acid that conforms to the formula




Ingredient CAS No. Definition & Structure Function(s) Glyceryl Ethylhexanoate/Stearate/ Adipate

glycerin esterified with a blend of 2-ethylhexanoic acid, stearic acid and adipic acid

wherein RC(O)- represents the residue of 2-ethylhexanoic, stearic, or adipic acid

skin-conditioning agent - occlusive

Glyceryl Heptanoate 26402-24-4

the glyceryl ester of heptanoic acid that conforms to the formula:


Glyceryl Hydrogenated Rapeseedate

the monoester of glycerin and the fatty acids derived from hydrogenated rapeseed oil

wherein RC(O)- represents the residue of the fatty acids derived from hydrogenated rapeseed oil


Glyceryl Hydrogenated Rosinate the monoester of glycerin and hydrogenated mixed long chain acids derived from rosin

wherein RC(O)- represents the residue of the hydrogenated mixed long chain acids derived from rosin


Glyceryl Hydrogenated Soyate the monoester of glycerin and hydrogenated mixed long chain acids derived from soy

wherein RC(O)- represents the residue of the hydrogenated mixed long chain acids derived from soy


Glyceryl Hydroxystearate 1323-42-8

the monoester of glycerin and hydroxystearic acid. It conforms generally to the formula


Glyceryl Isopalmitate the monoester of glycerin and a branched chain 16 carbon aliphatic acid. It conforms to the formula

one example of an “iso”


Glyceryl Isostearate 61332-02-3 66085-00-5

the monoester of glycerin and isostearic acid. It conforms generally to the formula

one example of an “iso”




Ingredient CAS No. Definition & Structure Function(s) Glyceryl Isotridecanoate/Stearate/Adipate

glycerin esterified with a blend of isotridecanoic acid, stearic acid and adipic acid

wherein RC(O)- represents the residue of isotridecanoic, stearic, or adipic acid


Glyceryl Lanolate the monoester of glycerin and lanolin acid

wherein RC(O)- represents the residue of lanolin acid

hair conditioning agent; skin-conditioning agent - emollient; surfactant - emulsifying agent

Glyceryl Laurate 142-18-7 27215-38-9 37318-95-9

the monoester of glycerin and lauric acid. It conforms generally to the formula


Glyceryl Laurate SE a self-emulsifying grade of Glyceryl Laurate that contains some sodium and/or potassium laurate

surfactant – emulsify-ing agent

Glyceryl Laurate/Oleate the monoester of glycerin esterified with a blend of lauric and oleic acids

wherein RC(O)- represents the residue of lauric or oleic acid


Glyceryl Linoleate 2277-28-3 26545-74-4 37348-65-5

the monoester of glycerin and linoleic acid. It conforms to the formula


Glyceryl Linolenate 18465-99-1 56554-41-7

the monoester of glycerin and linolenic acid. It conforms to the formula


Glyceryl Montanate 68476-38-0 71035-02-4

the monoester of glycerin and montan acid wax

wherein RC(O)- represents the residue of montan acid wax


Glyceryl Oleate 111-03-5 161403-66-3 25496-72-4 37220-82-9 68424-61-3

the monoester of glycerin and oleic acid. It conforms generally to the formula

fragrance ingredient; skin-conditioning agent - emollient; surfactant – emulsify-ing agent

Glyceryl Oleate SE a self-emulsifying grade of Glyceryl Oleate that contains some sodium and/or potassium oleate


Glyceryl Oleate/Elaidate a mixture of monoglycerides of oleic and elaidic acids

wherein RC(O)- represents the residue of elaidic or oleic acid




Ingredient CAS No. Definition & Structure Function(s) Glyceryl Olivate the monoester of glycerin and the fatty acids derived from olive oil. It conforms


wherein RC(O)- represents the fatty acids derived from olive oil


Glyceryl Palmitate 26657-96-5 542-44-9

the monoester of glycerin and palmitic acid. It conforms to the formula


Glyceryl Palmitate/Stearate 68002-71-1

the monoester of glycerin esterified with a blend of palmitic and stearic acids

wherein RC(O)- represents the residue of palmitic or stearic acid


Glyceryl Palmitoleate the monoester of glycerin and palmitoleic acid. It conforms to the formula


Glyceryl Pentadecanoate 122636-37-7

the monoester of glycerin and pentadecanoic acid. It conforms generally to the formula


Glyceryl Ricinoleate 1323-38-2 141-08-2 5086-52-2

the monoester of glycerin and ricinoleic acid. It conforms generally to the formula


Glyceryl Ricinoleate SE a self-emulsifying grade of glyceryl ricinoleate containing sodium and/or potassium stearate.


Glyceryl Rosinate 8050-31-5

the monoester of glycerin and mixed long chain acids derived from rosin

wherein RC(O)- represents the residue of mixed long chain acids derived from rosin

depilating agent; fragrance ingredient; skin-conditioning agent - emollient; surfactant - emulsifying agent

Glyceryl Stearate 11099-07-3 123-94-4 31566-31-1 85666-92-8

the monoester of glycerin and stearic acid. It conforms generally to the formula

fragrance ingredient; skin-conditioning agent – emollient; sur-factant - emulsifying agent

Glyceryl Stearate SE 11099-07-3 85666-92-8

a self-emulsifying grade of glyceryl stearate that contains some sodium and/or potassium stearate

surfactant - emulsifying agent



Ingredient CAS No. Definition & Structure Function(s) Glyceryl Stearate/Malate the ester of glycerin esterified with a blend of stearic and malic acids

wherein RC(O)- represents the residue of stearic or malic acid


Glyceryl Tallowate the monoester of glycerin and tallow fatty acids. It conforms generally to the formula

wherein RC(O)- represents the residue of the fatty acids derived from tallow


Glyceryl Undecylenate 123759-97-7 62285-15-8

the ester of glycerin and undecylenic acid that conforms to the formula


Table 3. Components Previously Reviewed Component Conclusion Reference Glycerin safe in cosmetics in the present practices of use and concentration (was used in 15,654 formulations,

10,046 of which were leave-ons; the maximum use concentrations were 79.2% in leave-on products, 99.4% in rinse-off products, and 47.9% in products diluted for the bath

8

Acetic Acid safe in the present practices of use and concentration 9 Adipic Acid safe in the present practices of use and concentration 10 Alginic Acid safe in the present practices of use and concentration 11 Citric Acid safe in the present practices of use and concentration 12 Coconut Acid safe for use in cosmetic products 13 Hydrogenated Rapeseed Oil safe in the present practices of use and concentration 14 Hydrogenated Soybean Oil safe in the present practices of use and concentration 14 Hydroxystearic Acid safe as a cosmetic ingredient in the present practices of use 15 Isostearic Acid safe as a cosmetic ingredient in the present practices of use 16 Lactic Acid safe for use in cosmetic products at concentrations ≤10%, at final formulation pH ≥3.5, when formulated to

avoid increasing sun sensitivity or when directions for use include the daily use of sun protection. These ingredients are safe for use in salon products at concentrations ≤30%, at final formulation pH ≥3.0, in products designed for brief, discontinuous use followed by thorough rinsing from the skin, when applied by trained professionals, and when application is accompanied by directions for the daily use of sun protection

17

Lanolin Acid safe for topical application to humans in the present practice of use and concentration 18 Lauric Acid safe in the present practices of use and concentration 19 Malic Acid safe for use as a pH adjuster in cosmetic formulations; data are insufficient to determine the safety for any

other functions 7

Oleic Acid safe in the present practices of use and concentration 19 Olea Europaea (Olive) Fruit Oil safe in the present practices of use and concentration 14 Palmitic Acid safe in the present practices of use and concentration 19 Ricinoleic Acid safe in the present practices of use and concentration 5 Stearic Acid safe in the present practices of use and concentration 19


Table 4. Current and historical frequency and concentration of use according to duration and exposure # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) Glyceryl Alginate Glyceryl Behenate 201527 19986 201428,29 19996 201527 19986 201428,29 19996 Totals* NR 1 NR 0.5 90 NR 0.27-2.5 2-5 Duration of Use Leave-On NR 1 NR 0.5 81 NR 0.3-2.5 2-5 Rinse-Off NR NR NR NR 9 NR 0.27 NR Diluted for (Bath) Use NR NR NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR 20 NR 0.3-1.5 2 Incidental Ingestion NR NR NR NR 7 NR NR NR Incidental Inhalation-Spray NR 1a NR 0.5b 22a; 13b NR 0.48a 5a Incidental Inhalation-Powder NR NR NR 0.5b 13b NR 0.45-2c NR Dermal Contact NR 1 NR 0.5 65 NR 0.3-2.5 NR Deodorant (underarm) NR NR NR NR NR NR NR 5 Hair - Non-Coloring NR NR NR NR 3 NR 0.48 NR Hair-Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR 2 NR 0.27 NR Mucous Membrane NR NR NR NR 7 NR NR NR Baby Products NR NR NR NR NR NR NR NR Glyceryl Caprate Glyceryl Caprylate 201527 19986 201428,29 19996 201527 19986 201428,29 19996 Totals* 57 NR 1 NR 190 NR 0.001-1.5 NR Duration of Use Leave-On 46 NR 1 NR 177 NR 0.001-1.5 NR Rinse-Off 11 NR NR NR 13 NR 0.01-1.5 NR Diluted for (Bath) Use NR NR NR NR NR NR NR NR Exposure Type Eye Area 4 NR NR NR 29 NR 0.03-1 NR Incidental Ingestion 7 NR NR NR 20 NR 0.3-1 NR Incidental Inhalation-Spray 7a; 8b NR 1 NR 33a; 37b NR 1a NR Incidental Inhalation-Powder 8b; 1c NR NR NR 16; 37b NR 0.98; 0.001-1c NR Dermal Contact 50 NR NR NR 161 NR 0.001-1.5 NR Deodorant (underarm) 5a NR pump spray: 1 NR 2a NR 1.5 NR Hair - Non-Coloring NR NR NR NR 6 NR 0.01-1 NR Hair-Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane 7 NR NR NR 20 NR 0.3-1 NR Baby Products 1 NR NR NR NR NR NR NR Glyceryl Caprylate/Caprate Glyceryl Citrate/Lactate/Linoleate/Oleate 201527 19986 201428,29 19996 201527 19986 201428,29 19996 Totals* 2 1 NR 2 NR NR 0.0004-0.004 NR Duration of Use Leave-On 1 1 NR NR NR NR NR NR Rinse-Off 1 NR NR NR NR NR 0.0004-0.004 NR Diluted for (Bath) Use NR NR NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR NR NR Incidental Inhalation-Spray 1 NR NR 2b NR NR 0.0004 NR Incidental Inhalation-Powder NR NR NR 2b NR NR NR NR Dermal Contact NR NR NR 2 NR NR NR NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair - Non-Coloring 1 NR NR NR NR NR 0.0004-0.004 NR Hair-Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane NR NR NR NR NR NR NR NR Baby Products NR NR NR NR NR NR NR NR


Table 4. Current and historical frequency and concentration of use according to duration and exposure # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) Glyceryl Cocoate Glyceryl Erucate 201527 19986 201428,29 19996 201527 19986 201428,29 19996 Totals* 14 1 1-2 0.3-5 NR NR NR 0.5 Duration of Use Leave-On 11 NR 2 0.3-2 NR NR NR 0.5 Rinse-Off 3 1 1-2 1-5 NR NR NR NR Diluted for (Bath) Use NR NR NR 1 NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR NR NR Incidental Ingestion NR NR NR 0.3-2 NR NR NR NR Incidental Inhalation-Spray 10b NR NR NR NR NR NR 0.5 Incidental Inhalation-Powder 10b NR NR NR NR NR NR 0.5b Dermal Contact 11 1 2 1-5 NR NR NR 0.5 Deodorant (underarm) NR NR 2 (pump spray) NR NR NR NR NR Hair - Non-Coloring 3 NR 1 NR NR NR NR NR Hair-Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane NR NR 2 0.3-4 NR NR NR NR Baby Products NR NR NR NR NR NR NR NR Glyceryl Ethylhexanoate/Stearate/Adipate Glyceryl Hydrogenated Rosinate 201527 201428,29 201527 19986 201428,29 19996 Totals* 39 0.6-3 29 NR 3-76.8 NR Duration of Use Leave-On 38 0.6-3 22 NR 3-10 NR Rinse-Off 1 NR 7 NR 65-76.8 NR Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area 21 0.8-3 14 NR 3-4.8 NR Incidental Ingestion 1 NR 6 NR 4-10 NR Incidental Inhalation-Spray 1a NR 1a NR 6.5a NR Incidental Inhalation-Powder 4 1-1.4 NR NR NR NR Dermal Contact 37 0.8-3 9 NR 65-76.8 NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 1 NR NR NR 6.5 NR Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane 1 NR 6 NR 4-10 NR Baby Products NR NR NR NR NR NR Glyceryl Hydroxystearate Glyceryl Isostearate 201527 19986 201428,29 19996 201527 19986 201428,29 19996 Totals* 14 32 0.5-2 0.8-2 104 53 0.3-2 0.3-6 Duration of Use Leave-On 14 22 0.5-2 0.8-2 14 53 0.8-2 0.5-6 Rinse-Off NR 10 NR NR 90 NR 0.3-1.5 0.3-3 Diluted for (Bath) Use NR NR NR NR NR NR NR 1 Exposure Type Eye Area 10 NR 1-2 2 4 23 NR 0.5-2 Incidental Ingestion 4a 1 NR NR 1 NR NR NR Incidental Inhalation-Spray NR 10a; 8b NR 0.8a; 2b 5a 3a; 1b NR 3a; 2b Incidental Inhalation-Powder NR 8b 0.5-0.9c 2b NR 1; 1b 0.8-1c 2b Dermal Contact 13 31 0.5-0.9 0.8-2 14 53 0.8-2 0.3-6 Deodorant (underarm) NR NR 0.9 (not spray) 2a NR NR NR NR Hair - Non-Coloring NR NR NR NR 1 NR 0.3 NR Hair-Coloring NR NR NR NR 78 NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane NR 2 NR NR 1 NR NR 1 Baby Products NR NR NR NR NR NR NR NR


Table 4. Current and historical frequency and concentration of use according to duration and exposure # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) Glyceryl Isotridecanoate/Stearate/Adipate Glyceryl Lanolate 201527 19986 201428,29 19996 201527 19986 201428,29 19996 Totals* 1 NR NR NR 1 3 NR NR Duration of Use Leave-On 1 NR NR NR 1 3 NR NR Rinse-Off NR NR NR NR NR NR NR NR Diluted for (Bath) Use NR NR NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR NR NR Incidental Inhalation-Spray 1a NR NR NR 1a 1a; 2b NR NR

Incidental Inhalation-Powder NR NR NR NR NR 2b NR NR Dermal Contact 1 NR NR NR 1 3 NR NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair - Non-Coloring NR NR NR NR NR NR NR NR Hair-Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane NR NR NR NR NR NR NR NR Baby Products NR NR NR NR NR NR NR NR Glyceryl Laurate Glyceryl Linoleate 201527 19986 201428,29 19996 201527 19986 201428,29 19996 Totals* 210 29 0.000065-4.5 0.1-4 87 17 0.000055-4.6 0.7-1 Duration of Use Leave-On 101 12 0.000065-0.5 0.4-4 70 13 0.000055-4.6 0.7-1 Rinse-Off 106 17 0.000065-4.5 0.1-4 17 4 NR 0.7-1 Diluted for (Bath) Use 3 NR 1 NR NR NR NR NR Exposure Type Eye Area 9 3 0.000065-0.48 0.1 8 1 2.5 NR Incidental Ingestion 8 NR NR NR 1 3 0.056-2.5 0.7 Incidental Inhalation-Spray 1; 24a; 10b 1; 5a 0.2a 1; 0.4a 1; 16a; 30b 1; 2a; 2b 0.000055-

0.0002a 1b

Incidental Inhalation-Powder 1; 10b; 3c NR 0.1-0.5c NR 30b; 2c 1 0.003-0.75b 1b Dermal Contact 176 20 0.000065-4.5 NR 64 14 0.0002-2.5 0.7-1 Deodorant (underarm) 15a 4a NR 0.1-4 NR NR NR NR Hair - Non-Coloring 26 9 0.088-1.5 0.3-2 17 NR 0.000055 NR Hair-Coloring NR NR NR NR 1 NR NR NR Nail NR NR NR NR 4 NR 0.019-4.6 NR Mucous Membrane 72 7 0.000065-4.5 0.3 2 3 NR 0.7 Baby Products 6 NR NR NR 2 NR NR NR Glyceryl Linolenate Glyceryl Oleate 201527 19986 201428,29 19996 201527 200250 201428,29 200450 Totals* 70 10 0.00045-0.4 0.7-1 663 112 0.0001-3 0.00002-5 Duration of Use Leave-On 55 9 0.00045-0.4 0.7-1 231 92 0.0001-3 0.00002-3 Rinse-Off 15 1 NR 0.7-1 411 19 0.1-2.7 0.02-5 Diluted for (Bath) Use NR NR NR NR 21 1 NR 0.2-3 Exposure Type Eye Area 7 1 0.2 NR 87 7 0.0075-2.3 0.008-0.01 Incidental Ingestion 1 3 0.046-0.2 0.7 34 18 0.0001-0.075 0.01-0.3 Incidental Inhalation-Spray 1; 12a; 20b 2a; 2b 0.00045a 1b 2; 48a; 22b 1; 27a; 20b 1.4; 0.0092a 0.0003;

0.00002-0.5a; 0.1-2b

Incidental Inhalation-Powder 20b; 2c 2b NR 1b 7; 22b; 2c 2; 20b 0.0028-3c 0.01-3; 0.1-2b Dermal Contact 47 7 0.09-0.2 0.7-1 493 73 0.0075-3 0.00002-3 Deodorant (underarm) NR NR NR NR NR NR 0.1-2.7 NR Hair - Non-Coloring 17 NR 0.00045 NR 118 21 0.0092-2.7 0.08-0.2 Hair-Coloring 1 NR NR NR 5 NR 2 0.02 Nail 4 NR 0.001-0.4 NR NR NR 0.015 NR Mucous Membrane 2 NR 0.046-0.2 0.7 262 19 0.0001-2.4 0.01-5 Baby Products 2 NR NR NR 13 2 NR 0.01-3


Table 4. Current and historical frequency and concentration of use according to duration and exposure # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) Glyceryl Oleate/Elaidate Glyceryl Palmitate 201527 19986 201428,29 19996 201527 19986 201428,29 19996 Totals* 4 NR NR 0.3-2 4 NR NR NR Duration of Use Leave-On 2 NR NR 0.3-2 3 NR NR NR Rinse-Off 2 NR NR NR 1 NR NR NR Diluted for (Bath) Use NR NR NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR NR NR Incidental Inhalation-Spray 2a NR NR 2a; 2b 3b NR NR NR Incidental Inhalation-Powder NR NR NR 2b 3b NR NR NR Dermal Contact 2 NR NR 0.3-2 4 NR NR NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair - Non-Coloring 2 NR NR NR NR NR NR NR Hair-Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane NR NR NR NR NR NR NR NR Baby Products NR NR NR NR NR NR NR NR Glyceryl Ricinoleate Glyceryl Ricinoleate SE 201527 20025 201428,29 20045 201527 20025 201428,29 20045 Totals* 42 16 1.5-15.2 2-12 NR NR 6.8 NR Duration of Use Leave-On 40 15 1.5-15.2 2-12 NR NR 6.8 NR Rinse-Off 2 1 NR NR NR NR NR NR Diluted for (Bath) Use NR NR NR NR NR NR NR NR Exposure Type Eye Area 10 7 1.5-11.6 2-12 NR NR 6.8 NR Incidental Ingestion 16 5 11.9-15.2 NR NR NR NR NR Incidental Inhalation-Spray 6a 1a; 2b NR 12a NR NR NR NR Incidental Inhalation-Powder NR 2b NR NR NR NR NR NR Dermal Contact 26 11 1.5-12.6 2-12 NR NR 6.8 NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair - Non-Coloring NR N NR NR NR NR NR NR Hair-Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane 18 5 11.9-15.2 NR NR NR NR NR Baby Products NR NR NR NR NR NR NR NR Glyceryl Rosinate Glyceryl Stearate 201527 19986 201428,29 19996 201527 19761 201428,29 19761 Totals* 50 4 0.018-96 0.06-12 5153 1371 0.0002-18.9 0.1-50 Duration of Use Leave-On 36 3 0.018-8 0.06-12 4229 1086 0.0002-17 0.1-50 Rinse-Off 14 1 2.6-96 3 914 284 0.006-18.9 0.1-25 Diluted for (Bath) Use NR NR NR NR 10 1 1-10 0.1-1 Exposure Type Eye Area 6 2 0.3-8 12 566 115 0.014-9 0.1-50 Incidental Ingestion 20 NR 0.48-0.5 6 30 NR 0.0002-3 NR Incidental Inhalation-Spray 2a NR NR NR 17; 1705a;

1380b 5; 308a; 212b 2-14; 0.5-4.8a;

2.3-6b 0.1-25; 0.1-

25a,b Incidental Inhalation-Powder 1 NR NR NR 20; 1380b;

28c 137; 212b;

11c 0.05-3; 2.3-6b;

0.0083-10c 0.1-25

Dermal Contact 23 2 0.018-96 0.6-10 4346 1167 0.0083-18.9 0.1-25; 0.1-25b Deodorant (underarm) NR NR NR NR 42a NR 0.25-17 NR Hair - Non-Coloring 1 NR 2.6 NR 318 97 0.15-4.8 0.1-25 Hair-Coloring 2 NR NR 3 200 29 0.9-7 0.1-10 Nail NR NR NR NR 11 15 0.006-6 1-50 Mucous Membrane 20 NR 0.48-0.5 0.4-6 182 36 0.0002-18 0.1-25 Baby Products NR NR NR NR 33 11 1.8 0.1-5


Table 4. Current and historical frequency and concentration of use according to duration and exposure # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) Glyceryl Stearate SE Glyceryl Stearate/Malate 201527 19761 201428,29 19761 201527 201428,29 Totals* 1420 217 0.001-10 0.1-25 NR 0.25 Duration of Use Leave-On 944 196 0.001-10 0.1-25 NR 0.25 Rinse-Off 476 21 0.5-6 0.1-25 NR NR Diluted for (Bath) Use NR NR 6 NR NR NR Exposure Type Eye Area 59 40 0.2-5 0.1-5 NR 0.25 Incidental Ingestion 1 NR NR NR NR NR Incidental Inhalation-Spray 1; 565a; 253b 1; 36a; 24b 3; 0.001-3a;

2-3.9b 1-5; 0.1-25a,b NR NR

Incidental Inhalation-Powder 253b; 3c 24b 2-3.9b; 0.2-10c 0.1-25b NR NR Dermal Contact 1013 205 0.2-10 0.1-25 NR 0.25 Deodorant (underarm) 1a NR NR NR NR NR Hair - Non-Coloring 45 7 0.001-4 1-25 NR NR Hair-Coloring 340 NR 3-6 NR NR NR Nail 1 NR NR NR NR NR Mucous Membrane 22 2 3-6 10-25 NR NR Baby Products 3 NR NR NR NR NR Glyceryl Undecylenate 201527 19986 201428,29 19996 Totals* 17 2 1 NR Duration of Use Leave-On 15 2 1 NR Rinse-Off 2 NR 1 NR Diluted for (Bath) Use NR NR NR NR Exposure Type Eye Area 2 NR NR NR Incidental Ingestion NR NR NR NR Incidental Inhalation-Spray 7a; 6b 2a NR NR Incidental Inhalation-Powder 6b NR NR NR Dermal Contact 14 2 1 NR Deodorant (underarm) NR NR NR NR Hair - Non-Coloring 2 NR NR NR Hair-Coloring NR NR NR NR Nail NR NR NR NR Mucous Membrane NR NR NR NR Baby Products NR NR NR NR

*Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types may not equal the sum of total uses. a Includes products that can be sprays, but it is not known whether the reported uses are sprays b Not specified whether this product is a spray or a powder or neither, but it is possible it may be a spray or a powder, so this information is captured for both categories of incidental inhalation c Includes products that can be powders, but it is not known whether the reported uses are powders NR – no reported use Table 5. Ingredients Currently Not Reported to be Used Glyceryl Acetate Glyceryl Adipate Glyceryl Alginate (was in use in 1998) Glyceryl Arachidate Glyceryl Cocoate/Citrate/Lactate Glyceryl Erucate (was in use in 1998) Glyceryl Ethylhexanoate Glyceryl Heptanoate Glyceryl Hydrogenated Rapeseedate Glyceryl Hydrogenated Soyate

Glyceryl Isopalmitate Glyceryl Laurate SE Glyceryl Laurate/Oleate Glyceryl Montanate Glyceryl Oleate SE Glyceryl Olivate Glyceryl Palmitate/Stearate Glyceryl Palmitoleate Glyceryl Pentadecanoate Glyceryl Tallowate


Table 6. Food Additive Status Ingredient CFR Citation GRAS Ingredients for Human Use Glyceryl Behenate 21CFR184.1328 Glyceryl Laurate 21CFR184.1505 Glyceryl Linoleate 21CFR184.1505 Glyceryl Oleate 21CFR184.1323 Glyceryl Palmitate 21CFR184.1324 Glyceryl Palmitate/Stearate 21CFR184.1329 Glyceryl Stearate 21CFR184.1324 GRAS Ingredients for Animal Use Glyceryl Caprate 21CFR582.4505 Glyceryl Caprylate/Caprate 21CFR582.4505 Glyceryl Laurate 21CFR582.4505 Glyceryl Laurate/Oleate 21CFR582.4505 Glyceryl Palmitate/Stearate 21CFR582.4505 Glyceryl Stearate 21CFR582.4505 21CFR582.1324 Direct Food Additives Glyceryl Hydrogenated Rapeseedate 21CFR172.736 Glyceryl Hydrogenated Rosinate 21CFR172.615 Glyceryl Hydrogenated Soyate 21CFR172.736 Glyceryl Rosinate 21CFR172.615; 21CFR172.735 Prior-Sanctioned Food Ingredients Glycerol Oleate 21CFR181.27 Indirect Food Additives Glyceryl Acetate 21CFR177.1200 Glyceryl Behenate 21CFR175.105; 21CFR176.210 Glyceryl Caprate 21CFR175.105; 21CFR176.180; 21CFR177.2800 Glyceryl Caprylate 21CFR175.105; 21CFR176.210 Glyceryl Caprylate/Caprate 21CFR175.105; 21CFR176.210; 21CFR177.2800 Glyceryl Cocoate 21CFR175.105; 21CFR176.210; 21CFR177.2800 Glyceryl Erucate 21CFR175.105 Glyceryl Hydrogenated Rosinate 21CFR178.3130 Glyceryl Hydroxystearate 21CFR175.105; 21CFR176.170; 21CFR176.200; 21CFR177.1200; 21CFR177.2800 Glyceryl Isopalmitate 21CFR175.105 Glyceryl Isostearate 21CFR175.105 Glyceryl Laurate 21CFR175.105; 21CFR176.210; 21CFR177.2800 Glyceryl Laurate/Oleate 21CFR175.105; 21CFR176.210; 21CFR177.2800 Glyceryl Linoleate 21CFR175.105 Glyceryl Linolenate 21CFR175.105 Glyceryl Oleate 21CFR175.105; 21CFR175.300; 21CFR175.320; 21CFR176.210; 21CFR177.2800 Glyceryl Palmitate 21CFR175.105 Glyceryl Palmitate/Stearate 21CFR175.105; 21CFR176.210; 21CFR177.2800 Glyceryl Palmitoleate 21CFR175.105 Glyceryl Ricinoleate 21CFR175.105; 21CFR176.170; 21CFR176.210; 21CFR178.3130 Glyceryl Rosinate 21CFR175.105; 21CFR175.300; 21CFR178.3120 Glyceryl Stearate 21CFR175.105; 21CFR175.210; 21CFR175.300; 21CFR176.200; 21CFR176.210; 21CFR176.210


Table 7. Penetration Enhancement Ingredient Test Compound Test System Results Reference Glyceryl Caprylate/Caprate 5-fluorouracil human abdominal skin samples

ability to enhance skin penetration was determined in vitro by measuring skin permeability coefficients

10-fold increase in penetration, as compared to the buffer control (statistically significant)

35

Glyceryl Isostearate 5-fluorouracil human abdominal skin samples (same protocol as above)

did not enhance penetration 35

Glyceryl Oleate 77.5% in a hexagonal gel phase

vitamin K, 2.5% porcine ear skin in Franz diffusion cells was compared to vaseline as a vehicle

2.2-fold increase to the stratum corneum (9 h); 3- and 2-fold increase to the epidermis + dermis after 3 and 12 h, respectively

36

15% in a nanodispersion of a hexagonal phase

2.7-fold increase to the stratum corneum (9 h); 3- and 3.7-fold increase to the epidermis + dermis after 3 and 12 h, respectively

Glyceryl Oleate 1:2 with PEG-40 hydrogenated castor oil

lidocaine, 2.5% hairless mouse skin in Franz diffusion cells

statistically significant increase in penetration 37

3:2 with PEG-40 stearate greater penetration than with above mixture Glyceryl Oleate, 5-20% in a propylene glycol solution

cisplatin, 0.05% porcine ear skin in Franz diffusion cells; full thickness skin and tape-stripped skin (stratum corneum removed) was used

did not act as a real penetration enhancer, but increased drug partition to the receptor solution, thereby improving transdermal penetration only a small enhancement was observed in skin without the stratum corneum as compared to intact skin

38

Glyceryl Oleate, 0.1-30% in propylene glycol

5-aminolevulinic acid, 5% full-thickness hairless mouse skin in diffusion cells

significantly increased in vitro skin permea-tion/retention

39

5-20% in propylene glycol 4-h application to dorsal area of hairless mice

concentration-dependent increase in photopor-phyrin IX (conversion product of test substance)


Table 8. Single Dose (Acute) Toxicity Studies Ingredient Animals/Group Concentration/Dose/Vehicle Procedure LD50/Results Reference

DERMAL Glyceryl Rosinate 4 male NZW rabbits 5 g/kg bw, in water 24-h patch; it was not stated

whether it was occlusive >5 g/kg bw no irritation observed

23

Glyceryl Rosinate 5 male NZW rabbits 10 g/kg bw, in water 24-h occlusive patch >10 g/kg bw no irritation observed

23

Glycerides, C16-18 and C18-hydroxy mono- and di-

5 Wistar rats 2 g/kg bw, neat 24-h occlusive patch >2 g/kg bw no irritation observed

20

ORAL Glyceryl Behenate 5 female Swiss mice 2 g/kg bw, neat by gavage >2 g/kg bw 21 glycerol ester of partially hydrogenated gum rosin

5 male Sprague-Dawley rats

2 g/kg bw in olive oil by gavage >2 g/kg bw 23

glycerol ester of partially hydrogenated gum rosin

5 male Sprague-Dawley rats

2 g/kg bw, neat by gavage >2 g/kg bw 23

Glyceryl Rosinate Sprague-Dawley rats, 5/sex

2 g/kg bw in vaselin oil by gavage >2 g/kg 23

Glyceryl Rosinate 10 male Sprague-Dawley rats

5 g/kg of a 10% w/v suspension in corn oil

by gavage >5 g/kg; urinary and fecal staining, soft stool and de-creased motor activity were observed for the first 48 h

51

Glyceryl Rosinate 10 rats 5 g/kg of a 10% w/v suspension in corn oil

by gavage >5 g/kg; urinary and fecal staining, soft stool, piloerec-tion, and decreased motor activity were observed for 1 wk, most notably for 24 h

52

Glyceryl Rosinate male Hilltop-Wistar albino rats; 3 (low dose) or 10 (high dose)

5 or 10 g/kg in 0.25% agar and 0.10% Tween 80

by gavage >10 g/kg 23

Glyceryl Stearate 5 female NMRI mice/sex

40 ml/kg bw; vehicle not stated

OECD guideline 401; given orally (details not provided)

>5 g/kg bw 20

Glyceryl Stearate 5 male NMRI mice not given OECD guideline 401 (details not provided)

>5 g/kg bw 20

Abbreviations: OECD – Organisation for Economic Co-operation and Development


Table 9. Repeated Dose Toxicity Studies Ingredient Animals/Group Study Duration Dose/Concentration Procedure Results Reference

ORAL Glyceryl Hydrogenated Rosinate

Sprague-Dawley rats, 20/sex in low dose group; 25/sex in all other groups

90 days mixed with corn oil (50:50); 2000, 5000, and 10,000 ppm in feed

dietary study; 5 control, mid- and high-dose animals/sex were killed at 30 days

NOAEL – 10,000 ppm no signs of toxicity

23


28 days 30% in 70% corn oil, given at 0.2% and 1.0%

dietary study NOEL – 1% no effect on mortality, morbidity, clinical signs, food consumption, or body weight gain; no gross or microscopic lesions

23


90 days 0.2, 1, and 5% in corn oil dietary study NOAEL – 1% decreased food consumption during the initial weeks of dosing in males an d females, increased liver weights in females, and in-creased relative liver-to-body weight in males in the high dose group

23

Glyceryl Rosinate Fischer 344 rats, 20/sex/group

90 days 625, 1250, and 2500 mg/kg/day

dietary study NOAEL – 2500 mg/kg/day no toxic effects

23

Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates

10 male and 5 female Wistar Han rats - recovery group with an additional 5 males and females in the control and high dose group

28 days 0, 100, 300 and 1000 mg/kg/day; on polyethyl-ene glycol

by gavage NOAEL – 1000 mg/kg bw/day no clinical signs of toxicity; no toxicologically-relevant changes in hematology, clinical chemistry, organ weights, or gross or micro-scopic lesions

20

MUCOUS MEMBRANE EXPOSURE Glycerol Oleate 12 female rhesus

macaque monkeys 6 mos 5% dissolved in K-Y

warming gel intravaginal administration of 1 ml of gel containing 50 mg test article; administration was 2x/day for first 8 wks; after a 3-wk non-treatment period, dosing was 1x/day for 11 wks

no vaginal inflammation or mucosal lesions in cervical vaginal tissues

40

Abbreviations: NOAEL - no-observable adverse effect level; NOEL – no-observed effect level


Table 10. Genotoxicity studies Test Article Concentration/Vehicle Test System Procedure Results Reference

IN VITRO Glyceryl Acetate 100-10,000 µg/plate S. typhimurium TA100,

TA1535, TA1537, or TA98

Ames test not mutagenic 41

Glyceryl Acetate (89% pure)

500-5000 µg/ml in deionized water

CHO cells chromosomal aberration assay, with or without metabolic

not mutagenic 42

Glyceryl Acetate (89% pure)

501-5010 µg/ml, with metabolic activation 1500-5010 µg/ml, without metabolic activation vehicle - deionized water

CHO cells SCE assay not genotoxic with metabolic activation positive results without metabolic activation; a dose-dependent increase was observed in 2 trials, and a doubling of SCEs was produced with 5000 µg/ml

42

Glyceryl Laurate 6.25-5000 µg/plate in Tween 80/bidistilled water (0.1 ml/plate)

S. typhimurium TA 1535, TA 1537, TA 1538, TA 98 and TA 100

Ames test, with and without metabolic activation (OECD Guideline 471)

negative positive controls gave expected results

22

Glyceryl Rosinate 2.5-500 µg/plate (vehicle not specified)

S. typhimurium TA 1535, TA 1537, TA 1538, TA 98 and TA 100



43

Glyceryl Rosinate 50.7-507 µg/ml CHO cells mammalian chromosome aberration test, with (2 h incubation) and without (7.3 h incubation) metabolic activation (OECD Guideline 473)

not genotoxic positive controls gave expected results

43

Glyceryl Rosinate 5.08-102 µg/ml rat hepatocyte primary cell cultures

UDS test (OECD Guideline 482)

not genotoxic positive controls gave expected results

43

Acetic and fatty acid esters of glycerol

0.61-78 µg/plate (all S. typhimurium strains, without activation) 10-313 µg/plate (all S. typhimurium strains, with activation) 313-5000 µg/plate (E. coli, with and without activation) vehicle - acetone

S. typhimurium TA 1535, TA 1537, TA 98 and TA 100; E. coli WP2 uvr A



22

Glyceride, C14-18 and C16-22 unsaturated, mono- and di-

8-5000 µg/plate in Tween 80/bidistilled water

S. typhimurium TA 1535, TA 1537, TA1538, TA 98 and TA 100



20

Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates

6 h, with and without metabolic activation: 0.02, 0.39, 0.078 0.156 mg/ml 24 and 48 h without activation: 0.078, 0.156, 0.313, 0.625, 1.25, 2.5, 5.0 mg/mL vehicle: acetone

Chinese hamster lung fibroblasts

mammalian chromosome aberration test (OECD Guideline 473)


20

IN VIVO Glycerides, C16-18 and C18-hydroxy mono- and di-

1000, 5000,(24 h analysis) or 10,000 (24, 48,and 72 h analysis) mg/kg bw

7 male and female CFW 1 mice

micronucleus test; animals were dosed with a single 20 ml/kg bw by gavage


20

Abbreviations: CHO – Chinese hamster ovary; DMSO – dimethyl sulfoxide; OECD – Organisation for Economic Co-operation and Development; SCE – sister chromatid exchange; UDS – unscheduled DNA synthesis


Table 11. Dermal irritation and sensitization

Test Article Concentration/Dose # per Group Procedure Results Reference

DERMAL IRRITATION

NON-HUMAN Glyceryl Behenate neat 3 male NZW rabbits 4-h semi-occlusive patch applied to shaved and abraded

skin; 0.5 ml applied; animals were observed for up to 7 days not irritating slight erythema was observed in 1 animal at 24 h; no edema was observed

21


neat NZW rabbits, 2 males and 1 female

4-h occlusive patch applied to intact skin; 0.5 g applied; animals were observed for up to 72 h

not irritating no erythema or edema

23

Glyceryl Rosinate no vehicle, but moistened with distilled water

3 NZW rabbits 4-h semi-occlusive patch applied to intact skin; 0.5 g applied; animals were observed for up to 72 h


23

Glyceryl Rosinate neat 3 NZW rabbits 4-h semi-occlusive patch applied to intact and abraded skin; 0.5 g applied; animals were observed for up to 72 h

not a primary irritant; at most, a minimal irritant mean primary cutaneous irritation score was 0.6 slight to well-defined erythema was observed in damaged skin; slight erythema in intact skin

23

Glyceryl Rosinate neat 3 NZW rabbits 4-h semi-occlusive; 0.5 g applied to intact and abraded skin; animals were observed for up to 72 h

not a primary irritant; at most, a minimal irritant mean primary cutaneous irritation score was 0.3 slight to well-defined erythema was observed in damaged skin; slight erythema in intact skin

23

Glyceryl Rosinate no vehicle, but moistened with distilled water

NZW rabbits, 2 males and 1 female

24-h occlusive patch applied to intact skin; 0.5 g applied; animals were observed for up to 72 h


23

Glyceryl Stearate 75% in vaseline 3 NZW rabbits 4-h semi-occlusive patch; 0.5 ml applied; animals were observed for 72 h

no irritating no erythema or edema

20

HUMAN Glyceryl Stearate 5% emulsion in a mineral

oil/water mixture (50:50) 20 subjects a 12 mm Finn chamber containing 50 µl of the test article

was applied for 48 h to the volar forearm of each subject using adhesive tape; the test sites were evaluated 24 h after patch removal on a scale of 0-3; TEWL) was measured using an evaporimeter

no difference in erythema between treated and control sites; the median value for clinical erythema was 0 at the glyceryl stearate-treated site (with 5% of the observations having a score >1, i.e., slight erythema, spotty or diffuse) and 0.5 at the control site (with 10% of the observations having a score >1) no significant effect on TEWL when compared to the control

44

Glyceryl Stearate 5% emulsion in a mineral oil/water mixture (50:50)

27 subjects SLS (15% for 7 h) was used prior to application of the test article; 17-h patches were then applied to the SLS-treated skin

no difference in the erythema between treated and control site; with application to irritated skin, the median value for clinical erythema was 1 both at the glyceryl stearate-treated site and control site; 22% of the observations at the test site and 15% of the observations at the control site had a score >1 no significant effect on TEWL

44




SENSITIZATION NON-HUMAN


10% in corn oil 25% in petroleum jelly

5 male and 5 female Hartley guinea pigs

GPMT intradermal induction: 3 pairs of intradermal injections: 1) FCA with an equal volume of water; 2) test article (10%) in vehicle; 3) test article (10%) in a 50:50 mixture of FCA and vehicle topical induction: 6 days after intradermal induction, the test site was pre-treated with 10% SLS; a 48-h occlusive patch (25% test article) was applied the next day challenge: topical challenge with 24-h occlusive patches (25% test article) was performed after a 2-wk non-treatment period

not an irritant or a sensitizer 23


neat for induction 25% and 50% in in paraffin oil for challenge

female Hartley guinea pigs

as above not an irritant or a sensitizer 23

Glyceryl Rosinate intradermal induction: 7.5% topical induction: 83.3% topical challenge: 83.3% and 41.65% in a coconut oil product

20 female Dunkin-Hartley guinea pigs

GPMT intradermal induction: 3 pairs of intradermal injections: 1) FCA with an equal volume of water; 2)test article in vehicle; 3) test article in a 50:50 mixture of FCA and vehicle topical induction: 6 days after intradermal induction, the test site was pre-treated with SLS; a 48-h occlusive patch was applied the next day challenge: topical challenge with 48-h occlusive patches was performed after a 2-wk non-treatment period

not a sensitizer slight to well defined erythema was observed during the first 48 h in both control and test article-treated animals challenged at 83.3%; all animals appeared normal after 72 hour

23

Glyceryl Rosinate induction: 100% challenge: 6.25% and 12.5% in paraffin oil

15 female Dunkin-Hartley guinea pigs

GPMT induction: on day 0, test animals received 2 injections of FCA, the skin was abraded, and a 498-h semi-occlusive patch was applied; on day 7, a second 48-h semi-occlusive patch was applied challenge: topical challenge with 24-h semi-occlusive patches was performed after a 2-wk non-treatment period


Glyceride, C16-18 and C18 Mono- and Dihydroxy

induction: 50% in paraffin oil challenge: 25% in vaseline

20 female Pirbright white guinea pigs

induction: 1 intradermal (day 0) and 1 occlusive 48-h epicutaneous (day 7) exposure, with FCA challenge: 24 h occlusive patch applied 14 days after second induction exposure

not a sensitizer 20

HUMAN Glyceryl Behenate applied neat 93 subjects HRIPT; 0.2 g applied with an occlusive patch

9 24-h patches induction patches were applied (3x/wk for 3 wks); the challenge patch was applied to a previously untreated site after a 2-wk non-treatment period

not a sensitizer 21





not stated, assumed neat 202 subjects HRIPT induction: 24-h occlusive patches were applied 3x/wk for 3 wks challenge: patches were applied to the original site and a previously untreated site after a 2-wk non-treatment period


Glyceryl Rosinate not stated 25 male and 25 female subjects

HRIPT induction: patches were applied every other day, for a total of 15 applications challenge: 24-h patch was applied after a 2-wk non-treatment period


Glyceryl Rosinate not stated 100 male and 100 female subjects

Schwartz patch test 5 day exposure for induction; challenge after a 6-wk non-treatment period, a 48-h patch was applied


Abbreviations: FCA – Freund’s Complete Adjuvant; GPMT – guinea pig maximization test; HRIPT – human repeated insult patch test; ME – microemulsion; NZW – New Zealand White; OECD – Organisation for Economic Co-operation and Development; TEWL – transepidermal water loss


Table 12. Ocular irritation studies

Test Article Concentration #/Animals/Grp Method Results Reference NON-HUMAN

Glyceryl Behenate undiluted 3 male NZW rabbits

single instillation; 0.1 ml eyes were not rinsed

not irritating; slight lacrimation in all animals at 1 h and 1 animal at 24 h; no other ocular effects were observed

21

Glyceryl Palmitate/Stearate

undiluted 6 NZW rabbits single instillation; 0.1 ml eyes were not rinsed

not irritating 20

Glyceryl Rosinate undiluted 6 NZW rabbits single instillation; 100 mg slightly irritating; mild irritation (of the conjunctiva was observed in 4 rabbits at 24-h

23

Glyceryl Rosinate undiluted 6 NZW rabbits single instillation; 100 mg slightly irritating; slight signs of irritation to the cornea, iris, and the conjunctiva; conjunctival irritation did not fully reverse in 2 animals within 72 h

23

Abbreviations: NZW – New Zealand White; OECD – Organisation for Economic Co-operation and Development Table 13. Case Reports Ingredient Case History Patch Testing Reference Glyceryl Caprylate female with a history of facial eczema for several years

that occurred after application of a skin care cream; the cream was composed of 90% glyceryl caprylate, 6% glyceryl dicaprylate, 4% free glycerol, and <0.1% glyceryl tricaprylate

- a 24-h occlusive patch test with several allergen series and the patient’s products resulted in positive reactions to several compounds at 72 h - a subsequent ROAT with the patient’s own products, applied 2x/day for 1 wk, resulted in a distinct reaction (erythema and vesicles) with the product containing 90% glyceryl caprylate - additional patch testing with 5% glyceryl caprylate in pet gave a +++ reaction - further patch testing with 0.1 and 1.0% glyceryl caprylate (in pet) produced a + and +++ reaction , respectively - no reactions were observed in 3 control subjects patched tested with 5% in pet

45

Glyceryl Hydrogenated Rosinate

female with severe bullous eruption on the wrist and hand following repeated application of a medicated patch

- patch testing with a standard series, the patch, and con-stituents of the patch, including 20% glyceryl hydrogenated rosinate in pet resulted in a strong positive reaction (+++) to the patch and to glyceryl hydrogenated rosinate on days 2 and 4 - no reactions were observed in 5 control subjects

46

Glyceryl Isostearate female with a history of persistent itchy and scaly erythema on the lips that appeared after using 5 different lipsticks

- patient had positive patch test reactions to all 5 lipsticks and 4 ingredients from 2 of the formulations, including 1% glyceryl isostearate in pet. - no reactions were observed in 3 control subjects patched tested with the same ingredients

47

Glyceryl Rosinate female with history of venous eczematous ulcerations on both legs, with recurrent eczematous dermatitis presented with an ulcer after application of medicated wound dressings; patient had sensitivities to multiple compounds

- positive patch test (+) to a medicated patch and 20% glyceryl rosinate in pet.

48

Glyceryl Stearate female with dermatitis of the arms due to a body lotion that was originally used for months without an effect

- patch testing with the lotion had positive (+) results - subsequent testing with ingredients of the lotion resulted in positive reaction to 20% glyceryl stearate in pet (?+ at 48 h; + at 72 h) -no reactions were observed in 20 control subjects

49

Abbreviations: pet – petrolatum; ROAT - repeated open application test


REFERENCES 1. Elder RL (ed). Final report on the safety assessment of glyceryl stearate and glyceryl stearate/SE. J Am Coll Toxicol.

1982;1(4):169-192. http://www.cir-safety.org/ingredients.

2. Nikitakis J and Breslawec HP. International Cosmetic Ingredient Dictionary and Handbook. 15 ed. Washington, DC: Personal Care Products Council, 2014.

3. Elder RL (ed). Final report on the safety assessment of glyceryl oleate. J Am Coll Toxicol. 1986;5(5):391-413. http://www.cir-safety.org/ingredients.

4. Elder RL (ed). Final report on the the safety assessment of glyceryl ricinoleate. J Am Coll Toxicol. 1988;7(6):721-739. http://www.cir-safety.org/ingredients.

5. Andersen FA (ed). Final Report on the Safety Assessment of Ricinus Communis (Castor) Seed Oil, Hydrogenated Castor Oil, Glyceryl Ricinoleate, Glyceryl Ricinoleate SE, Ricinoleic Acid, Potassium Ricinoleate, Sodium Ricinoleate, Zinc Ricinoleate, Cetyl Ricinoleate, Ethyl Ricinoleate, Glycol Ricinoleate, Isopropyl Ricinoleate, Methyl Ricinoleate, and Octyldodecyl Ricinoleate. Int J Toxicol. 2007;26(Suppl 3):31-77. http://www.cir-safety.org/ingredients.

6. Andersen FA (ed). Final Report of the Amended Safety Assessment of Glyceryl Laurate, Glyceryl Laurate SE, Glyceryl Laurate/Oleate, Glyceryl Adipate, Glyceryl Alginate, Glyceryl Arachidate, Glyceryl Arachidonate, Glyceryl Behenate, Glyceryl Caprate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Citrate/lactate/Linoleate/Oieate, Glyceryl Cocoate, Glyceryl Collagenate, Glyceryl Erucate, Glyceryl Hydrogenated Rosinate, Glyceryl Hydrogenated Soyate, Glyceryl Hydroxystearate, Glyceryl lsopalmitate, Glyceryl lsostearate, Glyceryl lsostearate/Myristate, G lyceryl lsostearates, G lyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Montanate, Glyceryl Myristate, Glyceryl lsotridecanoate/Stearate/ Adipate, Glyceryl Oleate SE, Glyceryl Oleate/Eiaidate, Glyceryl Palmitate, Glyceryl Palmitate/Stearate, Glyceryl Palmitoleate, Glyceryl Pentadecanoate, Glyceryl Polyacrylate, Glyceryl Rosinate, Glyceryl Sesquioleate, Glyceryi/Sorbitol Oleate/Hydroxystearate, Glyceryl Stearate/Acetate, Glyceryl Stearate/Maleate, Glyceryl Tallowate, Glyceryl Thiopropionate, and Glyceryl Undecylenate. Int J Toxicol. 2004;23(Suppl 2):55-94.

7. Andersen FA (ed). Final report on the safety assesment of malic acid and sodium malate. Int J Toxicol. 2001;20(Suppl 1):47-55. http://www.cir-safety.org/ingredients.

8. Becker LC, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, and Gill LJ. Safety assessment of glycerin as used in cosmetics. 2015. http://www.cir-safety.org/ingredients. Date Accessed 8-23-2015. Available on the CIR website.

9. Heldreth BA, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the Cosmetic Ingredient Review Expert Panel on the safety assessment of methyl acetate. Int J Toxicol. 2012;31(Suppl 1):112S-136S. http://www.cir-safety.org/ingredients.

10. Fiume MM, Heldreth BA, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the Cosmetic Ingredient Review Expert Panel on the safety assessment of dicarboxylic acids, salts, and esters. Int J Toxicol. 2012;31(Suppl 1):5S-76S. http://www.cir-safety.org/ingredients.

11. Johnson WJ Jr, Heldreth BA, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, and Gill LJ. 2015. Safety assessment of polysaccharide gums as used in cosmetics (Tentative report issued by the CIR Expert Panel). Available on the CIR website. Tentative report expected to be made final at the Sept 2015 CIR Expert Panel meeting.

12. Fiume MM, Heldreth BA, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Safety assessment of citric acid, inorganic citrate salts, and alkyl citrate esters as used in cosmetics. Int J Toxicol. 2014;33(Suppl 2):16S-46S. http://www.cir-safety.org/ingredients.

13. Burnett CL, Bergfeld WF, Belsito DV, Klaassen CD, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report on the safety assessment of Cocos nucifera (coconut) oil and related ingredients. Int J Toxicol. 2011;30(Suppl 1):5S-16S. http://www.cir-safety.org/ingredients.

14. Burnett CL, Fiume MM, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. 2011. Final report on the safety assessement of plant-dervied fatty acid oils as used in cosmetics. Available on the CIR website.













15. Andersen FA (ed). Amended final report on the safety assessment of hydroxystearic acid. Int J Toxicol. 1999;18(Suppl 1):1-10. http://www.cir-safety.org/ingredients.

16. Elder RL (ed). Final report on the safety assessment of isostearic acid. J Am Coll Toxicol. 1983;2(7):61-74. http://www.cir-safety.org/ingredients.

17. Andersen FA (ed). Final report on the safety assessment of glycolic acid, ammonium, calcium, potassium, and sodium glycolates, methyl, ethyl, propyl, and butyl glycolates, and lactic acid, ammonium, calcium, potassium, sodium, and TEA-lactates, methyl, ethyl, isopropyl, and butyl lactates, and lauryl, myristyl, and cetyl lactates. Int J Toxicol. 1998;17(Suppl 1):1-241. http://www.cir-safety.org/ingredients.

18. Elder RL (ed). Final report of the safety assessment for acetylated lanolin alcohol and related compounds. J Environ Pathol Toxicol. 1980;4(4):63-92. http://www.cir-safety.org/ingredients.

19. Elder RL (ed). Final report on the safety assessment of oleic acid, lauric acid, palmitic acid. myristic acid, and stearic acid. J Am Coll Toxicol. 1987;6(3):321-401. http://www.cir-safety.org/ingredients.

20. European Chemical Agency (ECHA). Stearic acid, monoester with glycerol (CAS No. 31566-31-1; glyceryl stearate). http://apps.echa.europa.eu/registered/data/dossiers/DISS-9c7f326e-20f4-1eb1-e044-00144f67d249/DISS-9c7f326e-20f4-1eb1-e044-00144f67d249_DISS-9c7f326e-20f4-1eb1-e044-00144f67d249.html. Last Updated 2013. Date Accessed 7-23-2015.

21. European Chemical Agency (ECHA). Docosanoic acid, ester with 1,2,3-propanetriol (77538-19-3; glyceryl behenate). http://apps.echa.europa.eu/registered/data/dossiers/DISS-dcee0b84-aa0b-5bf9-e044-00144f67d031/DISS-dcee0b84-aa0b-5bf9-e044-00144f67d031_DISS-dcee0b84-aa0b-5bf9-e044-00144f67d031.html. Last Updated 2013. Date Accessed 7-23-2015.

22. European Chemical Agency (ECHA). 2,3-Dihydroxypropyl laurate (CAS No. 142-18-7; glyceryl laurate). http://apps.echa.europa.eu/registered/data/dossiers/DISS-dffb4072-e286-47ae-e044-00144f67d031/DISS-dffb4072-e286-47ae-e044-00144f67d031_DISS-dffb4072-e286-47ae-e044-00144f67d031.html. Last Updated 2015. Date Accessed 7-27-2015.

23. European Chemical Agency (ECHA). Resin acids and Rosin acids, esters with glycerol (CAS No. 8050-31-5). http://apps.echa.europa.eu/registered/data/dossiers/DISS-97d6cc4e-2e09-6585-e044-00144f67d031/DISS-97d6cc4e-2e09-6585-e044-00144f67d031_DISS-97d6cc4e-2e09-6585-e044-00144f67d031.html. Last Updated 2015. Date Accessed 8-30-2015.

24. Ganem-Quintanar A, Quinianar-Guerrero D, and Buri P. Monoolein: A review of the pharmaceutical applications. Drug Development and Industrial Pharmacy. 2000;26(8):809-820.

25. Andersen FA (ed). Final Report of the Amended Safety Assessment of Glyceryl Laurate, Glyceryl Laurate SE, Glyceryl Laurate/Oleate, Glyceryl Adipate, Glyceryl Alginate, Glyceryl Arachidate, Glyceryl Arachidonate, Glyceryl Behenate, Glyceryl Caprate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Citrate/Lactate/Linoleate/Oleate, Glyceryl Cocoate, Glyceryl Collagenate, Glyceryl Erucate, Glyceryl Hydrogenated Rosinate, Glyceryl Hydrogenated Soyate, Glyceryl Hydroxystearate, Glyceryl Isopalmitate, Glyceryl Isostearate, Glyceryl Isostearate/Myristate, Glyceryl Isostearates, Glyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Montanate, Glyceryl Myristate, Glyceryl lsotridecanoate/Stearate/Adipate, Glyceryl Oleate SE, Glyceryl Oleate/Elaidate, Glyceryl Palmitate, Glyceryl Palmitate/Stearate, Glyceryl Palmitoleate, Glyceryl Pentadecanoate, Glyceryl Polyacrylate, Glyceryl Rosinate, Glyceryl Sesquioleate, Glyceryi/Sorbitol Oleate/Hydroxystearate, Glyceryl Stearate/Acetate, Glyceryl Stearate/Maleate, Glyceryl Tallowate, Glyceryl Thiopropionate, and Glyceryl Undecylenate. Int J Toxicol. 2004;23(Suppl 2):55-94. http://www.cir-safety.org/ingredients.

26. National Toxicology Program (NTP). Testing status of Acetin - 10780 - J (glyeryl acetate). http://ntp.niehs.nih.gov/testing/status/agents/ts-10780-j.html. Last Updated 2015. Date Accessed 7-23-2015.

27. Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients. FDA Database. 2015.

28. Personal Care Products Council. 4-29-2014. Concentration of Use by FDA Product Category: Glyceryl Monoesters. Unpublished data submitted Aug 7, 2015 by the Personal Care Products Council.

29. Personal Care Products Council. 1-6-2015. Concentration of Use by FDA Product Category: Glyceryl Esters (mixed). Unpublished data submitted by Personal Care Products Council. 1 pages.








http://apps.echa.europa.eu/registered/data/dossiers/DISS-9c7f326e-20f4-1eb1-e044-00144f67d249/DISS-9c7f326e-20f4-1eb1-e044-00144f67d249_DISS-9c7f326e-20f4-1eb1-e044-00144f67d249.html

http://apps.echa.europa.eu/registered/data/dossiers/DISS-9c7f326e-20f4-1eb1-e044-00144f67d249/DISS-9c7f326e-20f4-1eb1-e044-00144f67d249_DISS-9c7f326e-20f4-1eb1-e044-00144f67d249.html

http://apps.echa.europa.eu/registered/data/dossiers/DISS-dcee0b84-aa0b-5bf9-e044-00144f67d031/DISS-dcee0b84-aa0b-5bf9-e044-00144f67d031_DISS-dcee0b84-aa0b-5bf9-e044-00144f67d031.html

http://apps.echa.europa.eu/registered/data/dossiers/DISS-dcee0b84-aa0b-5bf9-e044-00144f67d031/DISS-dcee0b84-aa0b-5bf9-e044-00144f67d031_DISS-dcee0b84-aa0b-5bf9-e044-00144f67d031.html

http://apps.echa.europa.eu/registered/data/dossiers/DISS-dffb4072-e286-47ae-e044-00144f67d031/DISS-dffb4072-e286-47ae-e044-00144f67d031_DISS-dffb4072-e286-47ae-e044-00144f67d031.html

http://apps.echa.europa.eu/registered/data/dossiers/DISS-dffb4072-e286-47ae-e044-00144f67d031/DISS-dffb4072-e286-47ae-e044-00144f67d031_DISS-dffb4072-e286-47ae-e044-00144f67d031.html

http://apps.echa.europa.eu/registered/data/dossiers/DISS-97d6cc4e-2e09-6585-e044-00144f67d031/DISS-97d6cc4e-2e09-6585-e044-00144f67d031_DISS-97d6cc4e-2e09-6585-e044-00144f67d031.html

http://apps.echa.europa.eu/registered/data/dossiers/DISS-97d6cc4e-2e09-6585-e044-00144f67d031/DISS-97d6cc4e-2e09-6585-e044-00144f67d031_DISS-97d6cc4e-2e09-6585-e044-00144f67d031.html


http://ntp.niehs.nih.gov/testing/status/agents/ts-10780-j.html

30. Johnsen MA. The influence of particle size. Spray Technol Marketing. 2004;14(11):24-27.

31. Rothe H. Special Aspects of Cosmetic Spray Evalulation. 9-26-2011. Unpublished data presented at the 26 September CIR Expert Panel meeting. Washington, D.C.

32. Bremmer HJ, Prud'homme de Lodder LCH, and Engelen JGM. Cosmetics Fact Sheet: To assess the risks for the consumer; Updated version for ConsExpo 4. 2006. Report No. RIVM 320104001/2006. pp. 1-77.

33. Rothe H, Fautz R, Gerber E, Neumann L, Rettinger K, Schuh W, and Gronewold C. Special aspects of cosmetic spray safety evaluations: Principles on inhalation risk assessment. Toxicol Lett. 2011;205(2):97-104.

34. European Commission. CosIng database; following Cosmetic Regulation No. 1223/2009. http://ec.europa.eu/consumers/cosmetics/cosing/. Last Updated 2015. Date Accessed 8-7-2015.

35. Cornwell PA, Tubek J, van Gompel HAHP, Little CJ, and Wiechers JW. Glyceryl monocaprylate/caprate as a moderate skin penetration enhancer. International Journal of Pharmaceutics. 1998;171(2):243-255.

36. Lopes LB, Speretta FF, and Bentley MV. Enhancement of skin penetration of vitamin K using monoolein-based liquid crystalline systems. Eur J Pharm Sci. 2007;32(3):209-215.

37. Sintov AC and Shapiro L. New microemulsion vehicle facilitates percutaneous penetration in vitro and cutaneous drug bioavailability in vivo. J Control Release. 3-5-2004;95(2):173-183.

38. Simonetti LDD, Gelfuso GM, Barbosa JCR, and Lopez RFV. Assessment of the percutanous penetration of cisplatin: The effect of monoolein and the drug skin penetration pathway. Eur J Pharm Biopharm. 2009;73(1):90-94.

39. Steluti R, De Rosa FS, Collett J, Tedesco AC, and Bentley MV. Topical glycerol monooleate/propylene glycol formulations enhance 5-aminolevulinic acid in vitro skin delivery and in vivo protophorphyrin IX accumulation in hairless mouse skin. Eur J Pharm Biopharm. 2005;60(3):439-444.

40. Schlievert PM, Strandberg KL, Brosnahan AJ, Peterson ML, Pambuccian SE, Nephew KR, Brunner KG, Schultz-Darken NJ, and Haase AT. Glyceryl monolaurate does not alter rhesus macaque (Macaca mulatta) vaginal lactobacilli and is safe for chronic use. Antimicrob Agents Chemother. 2008;52(12):4448-4454.

41. Haworth S, Lawlor T, Mortelmans K, Speck W, and Zeiger E. Salmonella mutagenicity test results for 250 chemicals. Environ Mutagen. 1983;Suppl 1:1-142.

42. Loveday KS, Lugo MH, Resnick MA, Anderson BE, and Zeiger E. Chromosome aberration and sister chromatid exchange tests in Chinese hamster ovary cells in vitro: II. Results with 20 chemicals. Environ Mol Mutagen. 1989;13(1):60-94.

43. Environmental Protection Agency (EPA). Detailed chemical results for Resin acids and Rosin acids,esters with glycerol; CAS No. 8050-31-5. http://ofmpub.epa.gov/oppthpv/quicksearch.display?pChem=100024. Last Updated 2015. Date Accessed 7-30-2015.

44. Bárány E, Lindberg M, and Lodén M. Unexpected skin barrier influence from nonionic emulsifiers. Int J Pharm. 2-15-2000;195(1-2):189-195.

45. Herbert VG, Spiro JM, Reich K, Steinkraus V, Karimi J, Martin V, and Breuer K. Glyceryl (mono)caprylate - a new contact allegen. Cotact Dermatitis. 2013;69(6):383-385.

46. Foti C, Bonamonte D, Conserva A, Casulli C, and Angelini G. Allergic contact dermatitis to glyceryl-hydrogenated rosinate in a topical plaster. Contact Dermatitis. 2006;55(2):120-121.

47. Inui S, Azukizawa H, and Katayama I. Recurrent contact cheilitis because of glyceryl isostearate, diisostearyl maleate, oleyl alcohol, and Lithol Rubine BCA in lipsticks. Contact Dermatitis. 2009;60(4):231-232.

48. Pereira TM, Flour M, and Goossens A. Allergic contact dermatitis from modified colophonium in wound dressings. Contact Dermatitis. 2007;56(1):5-9.

49. de Groot AC, van der Meeren HL, and Weyland JW. Cosmetic allergy from stearic acid and glyceryl stearate. Contact Dermatitis. 1988;19(1):77-78.


http://ec.europa.eu/consumers/cosmetics/cosing/

http://ofmpub.epa.gov/oppthpv/quicksearch.display?pChem=100024

50. Andersen FA (ed). Re-review document on glyceryl oleate. 2004. http://www.cir-safety.org/ingredients. Available on the CIR website.

51. Biodynamics, Inc. Acute oral toxicity study in rats with Zonester® 85 DB-3012 in Sprague-Dawley male albino rats. 1979. http://yosemite.epa.gov/oppts/epatscat8.nsf/by+Service/A27D3331EFBEB88B8525704B004F707A/$File/88000000139.pdf. Date Accessed 8-22-2015. Report No. 5787-79. pdf pages 7-18.

52. Biodynamics, Inc. Acute oral toxicity study in rats with Zonester® 85 NF-7015. 1979. http://yosemite.epa.gov/oppts/epatscat8.nsf/by+Service/A27D3331EFBEB88B8525704B004F707A/$File/88000000139.pdf. Date Accessed 8-22-2015. Report No. 5788-79. pdf pages 18-21.



http://yosemite.epa.gov/oppts/epatscat8.nsf/by+Service/A27D3331EFBEB88B8525704B004F707A/$File/88000000139.pdf




JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY Volume 1, Number 4, 1982 Mary Ann Liebert, Inc., Publishers

Final Report on the Safety Assessment of Glyceryl Stearate and Glyceryl Stearate/SE

Glyceryl Stearate and Glyceryl Stearate/SE are the esterification products of glycerine and stearic acid, and are used in cosmetic formulations as emollients, emulsifiers, and stabilizers. In acute oral toxicity studies in rats, both ingredients were slightly toxic. Glyceryl Stearate in the diet of rats for three consecutive generations had no adverse effects. Five percent Glyceryl Stearate did not promote the carcinogenicity of DMBA in mouse skin. In subchronic and chronic dermal toxicity tests, Glyceryl Stearate was nontoxic to rabbits but did cause moderate irritation. Primary eye irritation studies, at concentrations up to lOOOJo, were mildly irritating or nonirritating to rabbits. Single andRepeated Insult Patch Tests showed both ingredients to be nonsensitizing and nonirritating. Products containing 2% Glyceryl Stearate were nonphototoxic and nonphotoallergenic. On the basis of the available data, it is concluded that Glyceryl Stearate and Glyceryl Stearate/SE are safe for topical application to humans in the present practices of use and concentration.

CHEMISTRY

Description and Preparation

Glyceryl Stearate

GLYCERYL Stearate is the esterification product of glycerol and stearic acid. The monoglyceride can conform to either of the following structures:<•.•>

or

Glyceryl Stearate is prepared commercially by high temperature esterification of stearic acid and glycerol or by transesterification of an appropriate triglyceride with glycerine. <3 > Verkade and Van der Lee<•> mixed anhydrous glycerol with the methyl ester of stearic acid in a solution of 1 OJo sulfuric acid and sodium sulfate and added magnesium oxide to form the Glyceryl Stearate product. Bertoni et al. 151 reported a similar preparation, although he used a sodium methoxide catalyst and a pyridine solvent. Veikhertz 161 reacted stearic acid with anhydrous glycerol for 40 hat 200°C and extracted the Glyceryl Stearate in cold water. Cressey<» reported a method in which stearic acid triglyceride is hydrolyzed in the presence of an alkaline catalyst. Lichnerova< 7 > prepared the !-monoester by first reacting glycerol with acetone to form isopropylidene glycerol. With the hydroxy groups protected in the 2nd and 3rd positions, the one free primary alcohol group was esterified with the chloride salt of stearic acid. The resulting stearic ester was then partially hydrolyzed, resulting in the desired 1-glyceryl stearate.

In addition to these methods, Glyceryl Stearate can be extracted commercially from sea buckthorn, whale oil, and shark liver oil. <•·••>

169


COSMETIC INGREDIENT REVIEW

Glyceryl Stearate/Self-Emulsifying Glyceryl Stearate/Self-Emulsifying is the esterification product of glycerol and an excess of stearic

acid; the excess stearic acid is reacted with potassium hydroxide to produce an emulsifying soap. Glyceryl Stearate/SE is prepared by the controlled high-temperature esterification of glycerol and excess stearic acid or by partial saponification of a triglyceride. The excess stearic acid is neutralized with potassium hydroxide to yield a product which contains potassium stearate. <31

Properties

Glyceryl Stearate is a white or cream-colored wax-like solid with a faint odor and an agreeable fatty taste. It is soluble in alcohol, petroleum ether, benzene, acetone, and mineral oil but insoluble in water. Glyceryl Stearate is characterized by "plastic" flow at temperatures between 20° and SOOC. <3 · 7•11 •121 The chemical and physical properties of Glyceryl Stearate are summarized in Table 1.

Glyceryl Stearate has a polymorphic crystalline structure with three modifications: a low melting o: form and two higher melting forms, {3 and {3'. The o: form is the first to separate when molten glyceryl stearate is cooled. The o: form changes rapidly into the more stable {3 form, which in turn slowly changes into the most stable {3' form. <13

·141 Lichnerova< 71 reported a fourth, sub-o: form which

lacks a defined melting point and readily passes into the o: form. The transformation of the sub-o: form to the o: form was reversible; this is an exception to the rule of irreversible crystalline transformation.

Glyceryl Stearate/SE is a white to cream-colored wax-like solid. <31 Its physical and chemical properties are summarized in Table 2.

Reactivity

Glyceryl Stearate undergoes reactions typical of fatty acid esters including glycerolysis, hydrolysis, transesterification, and enzymatic cleavage. <2

•15

·161 Under favorable conditions, Glyceryl Stearate

can also autoxidize. <171 Glyceryl Stearate undergoes hydrolysis in aqueous media. <181

Analytical Methods

Glyceryl Stearate is frequently determined by chromatographic analyses. These include gas chromatography, reversed-phase partition chromatography, thin-layer chromatography, highperformance liquid chromatography, and absorption chromatography,<t•-m Glyceryl Stearate can be analyzed directly or converted, prior to gas chromatographic analysis, to a trimethyl silyl ether derivative. 1271 Glyceryl Stearate can also be added to acetyl nitrate in silicic acid and the nitrate derivative then separated by chromatographic methods.

Other analytical methods include x-ray diffraction, differential thermal analysis, periodimetry, periodic oxidation, electron spin resonance, and infrared spectroscopy. <2

·13

•14

·33

-36

' Forman and Grady<m identified Glyceryl Stearate from other compounds in pharmaceutical creams by a method of channel-type inclusion in urea.

Impurities

Both Glyceryl Stearate and Glyceryl Stearate/SE contain such reaction impurities as glycerol, stearic acid, and waterY' Commercial Glyceryl Stearate and Glyceryl Stearate/SE may contain glyceryl distearate ( 42-440Jo ), glyceryl tristearate (20-23 OJo ), free glycerol (3-5 OJo) and small quantities of soap (if an alkaline catalyst is used in its preparation). <21 Certain preparations of Glyceryl Stearate and Glyceryl Stearate/SE also contain mono-, di-, and triesters of palmitic, oleic, and myristic acids, as well as unreacted fatty acids. The amount of these ester impurities is varied by the manufacturer to modify product stability and emulsification. Molecularly distilled Glyceryl Stearate contains over 900Jo of the monoester. 138

'

170


ASSESSMENT: GL YCERYL STEARATE AND GL YCERYL STEARATE/SE

TABLE l. PHYSICAL AND CHEMICAL PROPERTIES OF GLYCERYL STEARATE. a

Property

Molecular weight Melting point

a-form {1-form il'-form Commercial

Boiling point Density (glcm') Specific gravity (25°C) Refractive index pH(30fo) Acid valueb Iodine value Saponification value Fatty free acids Monoglycerides Glycerol Water

Value

358.57

74°C 81 oc 79°C 56°-58°C 238°-240°C 0.9841 0.97 1.400 9.309 1.5-3.0 0.5-4.0 160-177 <5% 40--50% 1.0-8.00/o l.OO!o (max.)

•oata from Refs. 3, 6, 12, 28-30. bThe acid value of Glyceryl Stearate increases as

the compound ages.''"

Additives

Both Glyceryl Stearate and Glyceryl Stearate/SE may contain 200 ppm butylated hydroxytoluene (BHT), which is added by the manufacturer as a preservative. <•J BHT is a Generally Recognized as Safe (GRAS) substance for which regulations have been issued under the Food, Drug and Cosmetic Act. <391 Its use in food as a GRAS food additive is limited to 0.020fo.

TABLE 2. PHYSICAL AND CHEMICAL PROPERTIES OF GLYCERYL STEARATE/SE.•

Property

Melting range Acid value Saponification value Combustion residue Free glycerine Iodine value Isobutane soluble material Free fatty acids Combined glycerol Monoglycerides Potassium Stearate Water Ionic character

•oata from Refs. 3, 32.

171

Value

50°-78°C 10-22 (max.) 138-170 0.1 O!o (max.) 6-100/o 3-60/o (max.) 85.7% 76.00/o 12.7% 30-450/o 5-12% 1% (max.) Nonionic/ Anionic



USE

Cosmetic Use

Purpose of Use Glyceryl Stearate and Glyceryl Stearate/SE are widely used in cosmetics. When applied to skin,

they produce a waxy, occlusive, water-soluble film, which makes it useful for hand lotions and creams. The viscosity of any emulsion that contains Glyceryl Stearate is directly proportional to the amount of Glyceryl Stearate present; Glyceryl Stearate is used to regulate the thixotropic index and viscosity of a cosmetic. Products that contain up to 307o Glyceryl Stearate are lotions, whereas those containing 10% Glyceryl Stearate are creams. Excessive skin defatting caused by the sulfates and sulfonates in detergent cleansing creams can be avoided by the presence of Glyceryl Stearate. Glyceryl Stearate base is used to stabilize a product, decrease water evaporation, make the product freeze-resistant, and keep it from forming surface crusts. Glyceryl Stearate also reduces the greasiness of oils used in certain cosmetic preparations. Glyceryl Stearate is used in cosmetic products as an opacifier, auxiliary oil/water emulsifier, acid stabilizer, and nonionic surfactant.< 11

·3 ..

38·40

"'01

Glyceryl Stearate/SE is used as an emulsifier and viscosity regulator. It needs no other auxiliary emulsifier to form a stable emulsion unlike Glyceryl Stearate, which requires such surfactants as soap to yield a stable preparation. <" 1

Scope and Extent of Use in Cosmetics According to the industry's voluntary submissions to the Food and Drug Administration (FDA) in

1976, Glyceryl Stearate and Glyceryl Stearate/SE are used in over 1200 and over 200 cosmetic formulations, respectively, in concentrations of ;=:0.1-50%. Table 3 summarizes the product formulation data for the two ingredients. <5' 1

TABLE 3. PRODUCT FORMULATION DATA.a

Ingredient/Cosmetic Product Type

Glyceryl Stearate Lotions, oils, powders, and creams Other bath preparations Eyeliner Eyeshadow Eye makeup remover Mascara

Other eye makeup preparations Perfumes

Powders Sachets Hair conditioners Permanent waves

Rinses

Shampoos

Concentration (percent)

172

>0.1-5 >0.1-1 >0.1-5 >0.1-10

> 1-5 >25-50 > 10-25 >5-10 > 1-5

>0.1-1 > 1-10 > 1-25

:s;0.1 >0.1-25 >0.1-10 >0.1-25

> 1-5 >0.1-1

> 1-5 >0.1-1

>5-10 > 1-5

>0.1-1

No. of product formulations

11 1

32 28

2 1 7

12 24 2 7 4 1

129 16 65

1 1 9 4 3 4 1


ASSESSMENT: GLYCERYL STEARATE AND GLYCERYL STEARATE/SE


Tonics and dressings

Hair dyes Rinses Bleaches Shampoos (coloring)

Blushers

Face powders

Foundations

Leg and body paints Makeup bases

Rouges

Skin care preparations (cleansing)

Depilatories Face, body, and hand

Hormone

Moisturizing

Night

Mud packs

Skin lighteners

Skin fresheners

Fixatives

TABLE 3. (Continued).


> 1-5 > 1-10 >5-10

::50.1 > 1-5 > 1-5

::5 0.1 > 1-5

>0.1-1 ::50.1 >0.1-1 ::50.1

> 1-5 >0.1-1 ::50.1

> 1-5 >5-10 > 1-5

>0.1-1 > 1-5

>0.1-1 > 10-25 >5-10 > 1-5

>0.1-1 ::50.1

> 1-5 > 10-25 >5-10 > 1-5

>0.1-1 > 1-5

>0.1-1 > 10-25 >5-10 > 1-5

>0.1-1 > 10-25 >5-10 > 1-5

>0.1-1 > 10-25 >5-10 > 1-5

> 10-25 >5-10 > 1-5 > 1-5

Other makeup preparations (not eye)

>0.1-1 > 1-5

>0.1-1 > 1-5

>0.1-1

173


6 3 2

24 1 1 1 7 5 3 2 6

89 13 5

15 1

36 8 2 1 7 6

64 27 2 2 4

15 151 42

2 1 2

16 183 49

1 6

35 3 2 9 5 4 1 2 1 1 1 1 4 6





Cuticle softeners

Nail creams and lotions

Bath soaps and detergents

Douches

Other personal cleanliness products

Aftershave lotions Shaving cream

Other shaving preparations Wrinkle removers Other skin care preparations

Suntan and sunscreen products (gels, creams, and liquids)

Indoor tanning Glyceryl Stearate!SE Eyeliners Eyeshadows Eye lotion Mascara Other eye makeup preparations Sachets

Other fragrance preparations Hair conditioners

Hair straighteners Blushers Foundations

Makeup bases

Other personal cleanliness products Aftershave lotions Skin care preparations (face, body, and hand)


> 10-25 >5-10 > 1-5

>25-50 > 10-25 > 1-5 > 1-5

s0.1 > 10-25 >5-10 > 1-5

>0.1-1 > 10-25 >5-10 > 1-5

>0.1-1 >0.1-1

> 1-5 >0.1-1

> 1-5 > 1-5

> 10-25 >5-10 > 1-5

>0.1-1 >5-10 > 1-5

>0.1-1 > 1-5

>0.1-1 > 1-5 > 1-5 > 1-5

>0.1-1 > 1-5

>0.1-1 >1-5

> 10-25 >5-10 > 1-5 >5-10

s0.1 > 1-5

>0.1-1 > 1-5

>0.1-1 > 10-25 >5-10

> 10-25 >5-10 > 1-5

s0.1

174


1 2 5 1 1 5 2 1 3 6 7 1 2 6 5 2 2 3 2 1 2 2 1

16 4 9

23 4 2

32 2 1 1 4

14 1 1 1 1 1 4 1

13 1 1

54 2 1 3 5

15 1


ASSESSMENT: GL YCERYL STEARATE AND GL YCERYL STEARA TE/SE

Hormone Moisturizing Night

Ingredient! Cosmetic Product Type

Skin lighteners Skin fresheners Other skin care preparations

Cleansing creams

• From Ref. 51.



>5-10 s0.1-25

> 1-5 >0.1-1

> 1-5 >0.1-5 > 10-25 > 1-5

>0.1-1 s0.1

>5-10 > 1-5

>0.1-1 s0.1

Non-Cosmetic Use


1 32 2 1 3 1 1 2 1 1 2 4 3 3

Glyceryl Stearate is used in food as a surfactant, emulsifier, flavor dispersant, antistalant, antisticking, and thickening agent. It is most widely used in bread for its emulsifying and surfactant properties; in baking products it serves as an antistalant and dough conditioner. <2

·"·52

•63

)

Glyceryl Stearate is a GRAS substance regulated by the Food, Drug and Cosmetic Act. <39) Its con

centration in food ranges from 0.01 to 2.00Jo; the possible average daily intake, based on the types of food consumed, is about 15 mg/kg for persons aged two or older and 150 mg/kg for infants. These estimates are considered to be maximum possible intakes; more realistically, a person is likely to ingest approximately 63 mg (or approximately 1 mg/kg) of Glyceryl Stearate daily. <64

)

Glyceryl Stearate is also approved as a specific indirect food additive, under regulation of the Food, Drug and Cosmetic Act. There are no specific limitations on the use in food of Glyceryl Stearate as a surface lubricant and as a defoamer in coatings intended for use in food production, packaging, treating, transporting, or holding (21 CFR 176.200, 21 CFR 175.300).

Glyceryl Stearate is used in pharmaceutical preparations as a solidifier and controled release agent. It is used in suppositories as a lipophile and as an agent to prevent sedimentation of dispersed solids. <6

s-7l) Glyceryl Stearate is used as a base in over-the-counter (OTC) topical analgesics (44 CFR 69771). Table 4 lists the non-cosmetic uses of Glyceryl Stearate.

BIOLOGICAL PROPERTIES

Bactericidal Properties

Glyceryl Stearate (1.50 ~tglml) did not inhibit growth of gram-positive bacteria. <?•) Weddeburn<") observed that in cosmetic preparations containing a preservative, and Glyceryl Stearate as a surfactant, the preservative's efficiency was reduced as the surfactant preservative ratio increased. He suggested that such nonionic surfactants as Glyceryl Stearate allow microorganisms to become resistant to preservatives.

Absorption, Metabolism, and Excretion

When ingested, monoglycerides are readily absorbed through the duodenal mucosa and converted to triglycerides. However, ingestion of 25 g of Glyceryl Stearate by human subjects caused no ap-

175



TABLE 4. NON-COSMETIC UsE OF GLYCERYL MONOSTEARATE AS DRUG-RELEASE AGENT, SURFACTANT, AND EMULSIFIER.

Drug Released/ In

Aminophenazone/Suppositories < 67 · 79-81 >

Azophen!Suppositories 18us> Salicylate/Suppositories! 93-96 >

Salicylate/Ointments138·'"' >

Oxytetracyclene/ Ointments<'"' 1

Sulfathiazole + Ephedrine/ Ointments1 1081

Sulfanilmide/Tablets1' 121

Sulfosalicylate/PVC Tablets Matrix1 "'·"61

Bromophenylamine Maleax/- 1 ' 20>

Ethyl Arninobenzoate/Dental Lotions 11221

Phenindion/Capsules 1 ' 241

Isoprenaline/Tablets 1 126 >

Morphine-Naltrexone/Tablets 1 1291

Acetylsalicylic Acid/Tablets 1 130·'3' >

Surfactant in

Tablets1821

Macaroni186-901 Bread(97,98}

Cakes1' 021

Dehydrated potatoes006> Coconut oil1' 091

Frying oils 1 " 3 >

White petroleum11171

Emulsifier in

Salves 1831

Liquid milk replacersl 52·9 .. 92

>

Ice cream199·'001

Ointments1 103·'041

Dentallotions1' 071

Cakes!''"·'''>

Bread11141

Pasta1" 8·1191

Margarine1 '20

Starch paste11231

Peanut butter< ' 2' 1

Food (general)< ' 27·1281

parent change in serum triglyceride concentrations. Only a slight increase occurred after ingestion of 50 g. Since stearic acid is a solid fat at body temperature, it may not be readily absorbed in the intestine. 1761

The effects of Glyceryl Stearate on kidney tissue and splenic enzymes have been studied. Gall 1771

reported that a solution of 0.5 mg/ml Glyceryl Stearate had no deleterious effect on monkey kidney tissue cultures. Blonder et al. 17"1 observed that Glyceryl Stearate did not inhibit glucocerebrosidase activity in vitro.

Oral Toxicity Acute

Animal Toxicology

Various high doses of Glyceryl Stearate and Glyceryl Stearate/SE at concentrations greater than those used in cosmetics, were practically nontoxic when administered to rats by gavage (Table 5).

Chronic When incorporated in the diet of rats at concentrations of 15-250Jo for three consecutive genera

tions, Glyceryl Stearate had no adverse effects on body weight, growth, and reproduction. In a simultaneous study, rats which consumed a diet containing 25% Glyceryl Stearate daily for two years developed renal calcifications and their liver weight increased.< 101

Dermal Toxicity Primary irritation The Draize method (or a modification of it), the Federal Hazardous Substances Labeling Act

(FHSLA) method, and the Department of Transportation (DOT) method were used to evaluate the potential skin irritancy of Glyceryl Stearate and Glyceryl Stearate/SE. These two substances were reported to be nonirritating or mildly irritating even when they were tested at 100 percent concentrations. The highest reported Primary Irritation Index (PII) was 1.80 out of a possible 4.00 (Table 6).

Subchronic toxicity Glyceryl Stearate (4-5%) was applied at 2 mllkg/day five days a week for four weeks to the

clipped abraded dorsal skin of six white rabbits. Comparison of mean body weights, clinical signs, hematological results, and gross pathology results showed no significant differences between

176


> [JJ [JJ

TABLE 5. ACUTE ORAL TOXICITY. tTi [JJ [JJ

Cone. No. of :.:: tTi

Compound (Percent) animals/Species Dose LD50 Commentsc Ref z :-:l

os• 33.3 in PGDDd 10 rats 10 g/kg > 10 g/kg 400Jo fatalities at 10 g/kg-mildly toxic/ 132 0 practically nontoxic r

....:: GS 33.3 in PGDD 10 rats 10 g/kg > 10 g/kg Practically nontoxic 133 (1

GS 33.3 in PGDD 10 rats 10 g/kg > 10 g/kg Practically nontoxic 134 tTi ~

GS 33.3 in corn oil 30 rats 1.0-32.0 g/kg >32.0 g/kg Relatively harmless 135 ....:: r

GS 20.0 in corn oil 30 rats 2-64 ml/kg >64 ml/kg Relatively harmless 135 [JJ

GS 2 (active 10 mice 15 mllkg > 15 mllkg Relatively harmless 136 -l tTi

(protective ingredient) > cream) ~ -.1 GS 100 5 rats (per grp) >5.0 g/kg Practically nontoxic 137 -.1 ;l GS 100 5 rats (per grp) >5.0 g/kg Practically nontoxic 137

GS/SP 33.3 in corn oil 30 rats 1.0-32.0 g/kg >32 g/kg Relatively harmless 138 > z GS/SE 33.3 in PGDD 10 rats 10 g/kg > 10 g/kg 40% fatalities at 10 g/kg-mildly toxic/ 139 0

practically nontoxic 0 GS/SE 25 in corn oil 15 rats 7.5 and 10 > 10 g/kg 40% fatalities at 10 g/kg-mildly toxic/ 140 r

....:: g/kg practically nontoxic (1

GS/SE 25 in PGDD 10 rats 10 g/kg > 10 g/kg Practically nontoxic 141 tTi ~

GS/SE 100 5 rats (per grp) >5 g/kg Practically nontoxic 137 ....:: r

"Glyceryl Stearate. [JJ

-l bGiyceryl Stearate/SE. tTi

> <According to Hodge and Sterner. ~ dPropylene glycol dicaprylate-dicaprate. -l tTi '-[JJ

tTi


TABLE 6. PRIMARY SKIN IRRITATION.

No. of Compound Protocol rabbits Cone. (Percent) PII Comments Ref

as• FHSLA 6 50 in corn oil 0 Nonirritating 138 GS FHSLA 6 100 0 Nonirritating 144 GS DOT 6 100 0 Nonirritating 144 (") GS Draize 6 100 0.208 Erythema only-mostly at 24 h-mildly irritating 134 0

en GS Draize 6 100 0.208 One rabbit only-erythema and edema ( 1 +)at 24 and 133 ~

72 h -mildly irritating ti:I ""'l

GS Draize (Mod) 2 100 0.625 Erythema and edema at 24 and 72 h- mildly irritating 132 -(") GS Ac 9 100 O.o39'i Minimally irritating 145 -GS A 9 20 in corn oil 0.039'i Minimally irritating 145 z a - GS Draize 3 3.0 in mineral oil o.s Erythema at 24 h only- mildly irritating 146 :;l:l

-.1 GS A 9 50 in corn oil 0.72d Mildly irritating 14S ti:I 00 0 GS A 9 SO in corn oil 0.11 Mildly irritating 137 -ti:I GS A 9 100 1.8 Mildly irritating 148 z GS A 9 100 1.6 Mildly irritating 148 ""'l

GS A 9 100 1.6 Mildly irritating 148 :;l:l ti:I

GS A 9 100 1.4 Mildly irritating 148 < GS A 9 100 1.2 Mildly irritating 148 63 GS A 9 100 l.S Mildly irritating 148 ~ GS A 9 100 1.4 Mildly irritating 148 GS A 9 100 1.33 Mildly irritating 148 GS A 9 100 0.33 Minimally irritating 148 GS A 9 SO in corn oil 0.06 Minimally irritating 148 GS Draize 3 2.0 (active o.s Erythema at 24 h only- mildly irritating 136 (Protective ingredient)

cream)


> Vl Vl m Vl Vl

GS (First A 3 5.0 (active 0.89 Mildly irritating 149 ~ m aid cream) ingredient) z

GS (Blemish A 9 13.8 (active 0.89 Mildly irritating 150 ::l stick) ingredient) 0

GS (Suntan A 9 2.0 (active 0.5 Mildly irritating 136 t'"" -<

lotion) ingredient) ()

GS/SEb Draize 6 100 0 Nonirritating 141 m :;c

GS/SE Draize 6 100 0 Nonirritating 140 -< GS/SE Draize 6 100 0.25 Mildly irritating 139 t'""

Vl GS/SE FHSLA 6 50 in corn oil 0 Nonirritating 144 -l m GS/SE FHSLA 6 50 in corn oil 0 Nonirritating 135 > GS/SE DOT 6 50 in corn oil 0 Nonirritating 135 :;c - GS/SE Draize (Mod) 3 5.0 in water 0 Nonirritating 146 >

-.1 @ '-0 GS/SE A 9 50 in corn oil 0.22d Mildly irritating 145 GS/SE A 9 50 in corn oil 0.50 Mildly irritating 137 > z GS/SE A 9 50 in corn oil 0.63 Mildly irritating 137 0 GS/SE A 9 50 in corn oil 0.66 Mildly irritating 137 0 GS/SE A 9 50 in corn oil 0.38 Mildly irritating 137 t'""

-< GS/SE A 9 50 in corn oil 0 Nonirritating 137 ()

GS/SE A 9 50 in corn oil 0.17 Minimally irritating 137 m :;c -<

"Glyceryl Stearate. t'""

bGlyceryl Stearate/SE. Vl -l

co.s ml applied to clipped intact back of each animal under occlusive patch. Patch removed at 24 h. Site scored at 24 and 72 h.' 1471 m > dMaximum score ( PII) = 4. :;c > -l m ' Vl m



Glyceryl Stearate-treated rabbits and untreated controls. Animals treated with the Glyceryl Stearate solution developed such moderate irritation as slight to moderate desquamation and slight to welldefined erythema in all animals and many cases of atonia and fissuring. 1 142

>

Chronic toxicity A 4-50Jo solution of Glyceryl Stearate was applied at 2 ml/kg/day five days a week for 13 weeks to

the clipped abraded dorsal skin of six white rabbits. Slight to moderate erythema, edema, atonia, and occasional fissuring occurred in all test animals. Dermatopathologic findings consisted of dermal inflammatory cell infiltrates, hyperkeratosis, and acanthosis. There were no changes in body weight, no gross toxic effects, no gross skin lesions, and no changes in organ weight attributable to the test material. It was concluded that the Glyceryl Stearate-solution was a moderate skin irritant. 1 143

>

Sensitization The Landsteiner/Jacobs Method and the Kligman Maximization Procedure were used to deter

mine the sensitizing potential of Glyceryl Stearate and Glyceryl Stearate/SE in guinea pigs. Glyceryl Stearate and Glyceryl Stearate/SE proved to be nonsensitizing (Table 7).

Eye Irritation The Draize procedure or a modification of it was used to evaluate the potential eye irritancy of

Glyceryl Stearate and Glyceryl Stearate/SE. The ingredient was instilled into one eye of each test rabbit. In four tests, some eyes were rinsed after the introduction of the test substance. Eye irritation was scored for a specified number of days after the ingredient was instilled. These studies indicate that Glyceryl Stearate and Glyceryl Stearate/SE are nonirritating to mildly irritating to the eye at concentrations up to 100%. The highest reported mean irritation score at any time was 7 (maximum score = 1 10) (Table 8).

Carcinogenicity Glyceryl Stearate was fed to 53 mice at doses of 50-100 mg daily until the animals died. Three mice

(5.6%) developed brain tumors on the upper surface of the frontal lobe, consisting mainly of differentiated nerve cells. Glyceryl Stearate (50-100 mg/day) plus cholesterol (4-5 mg/day) in the diet induced brain tumors in ten of 72 mice (13.8%). Of 80 mice fed 4-5 mg/day cholesterol alone, 20 developed brain tumors (25%) but none of the 188 control mice did. 1 152 >

A diet containing 1.5% Glyceryl Stearate was fed to mice daily until they died to determine if the ingredient induced gastric tumors. Two or 1.7% of the 115 mice developed forestomach papillomas. Two of the 195 control mice (1.0%) developed forestomach papillomas. 1153

>

Saffiotti and Shubik1154> tested the tumor promoting activity of Glyceryl Stearate on the clipped

dorsal skin of Swiss mice. One week after a single application of 9, 10-dimethylbenz(a)anthracene (DMBA) (1-1.5% in mineral oil), 5% Glyceryl Stearate (in acetone) was applied to skin twice weekly. No tumors developed; slight epidermal hyperplasia at the site of application was noted.

Glyceryl Stearate, administered orally in doses of 2.5 or 10 mg/day for five days, was not an effective antitumor agent in mice implanted with one-day-old Erlich ascites carcinomas. <155

>

Clinical Assessment of Safety

Single Insult Patch Test (SIPT) Seven lots of Glyceryl Stearate were tested for irritation on panels of 20 subjects each. A single oc

clusive patch containing the undiluted test material was applied to each subject's skin and left in place for 24 h. Patches were then removed and the skin sites scored for irritation. Of the 140 patches applied, only six resulted in irritation (no score was greater than 2 in a maximum of 4). The results indicated that undiluted Glyceryl Stearate is, at worst, a mild irritant. 1148

>

A blemish stick and a first aid cream containing 13.8% and 5.0% Glyceryl Stearate, respectively, were tested for potential skin irritancy using a SIPT. Each formulation was applied under occlusion to 20 subjects. The Plls for the blemish stick and first aid cream were 0.03 and 0.3, respectively (maximum score = 4.0), indicating mild irritation. 1 150

·159

>

A modified Maibach Cumulative Irritancy Test was used to study a hair product containing

180


TABLE 7. SENSITIZATION.

Dose! No. of Cone. No. of Induction Phases! Rest Challenge

Compound (percent) Method Guinea pigs Route/Time period (site) Comments Ref

as• 0.1 mll0.1 Lansteinerl Jacobs 2 lO injections; 2 weeks 0.05 ml Nonsensitizing 132 every other day (virgin)

GS 0.1 ml/0.1 Lansteinerl Jacobs 2 10 injections; 2 weeks 0.05 ml Nonsensitizing 133 every other day (virgin)

GS 0.1 ml/0.1 Lansteiner I Jacobs 2 10 injections; 2 weeks 0.05 ml Nonsensitizing 134 every other day (virgin) - GS sc Kligman Max. lO 6 applied to 2 weeks 0.5 ml Nonsensitizing 151 00

abraded skin; every other day

GSISEb 0.1 ml/0.1 Lansteiner I Jacobs 2 lO injections; 2 weeks 0.05 ml Nonsensitizing 141 every other day (virgin)

GS/SE 0.1 ml/0.1 Lansteiner I Jacobs 2 lO injections; 2 weeks 0.05 ml Nonsensitizing 140 every other day (virgin)

GS/SE 0.1 ml/0.1 Lansteinerl Jacobs 2 lO injections; 2 weeks 0.05 ml Nonsensitizing 139 every other day (virgin)

•olyceryl Stearate bGlyceryl Stearate/SE <Booster of 75f1/o OS in petrolatum (0.05 ml) applied occlusively for 48 hone week after last induction application.


TABLE 8. DRAIZE PRIMARY EYE IRRITATION.

Scores (Max = 110)

No. of Eye wash Day

Cone. (') Compound rabbits (Percent) YIN 1 h 1 2 3 4 5 Comments Ref 0 c:n

osa 9 100 y 0 0 0 0 0 0 Nonirritating 156 ~ tT1

GS 9 100 y 0 0 0 0 0 0 Nonirritating 144 ...., GS 6 100 N 0 0 0 Nonirritating 138 () GS 3 3.0 in mineral N 0 0 0 0 0 0 Nonirritating 157 -z

oil 0 00 GS 6 20 in corn oil N 1 1 1 0 0 Minimally irritating 145 § N GS 6 100 N 2 1 0 0 0 Minimally irritating 148 0 -GS 6 50 in corn oil N 6 3 1 0 0 Mildly irritating 137 tT1

GS (Suntan 3 2.0 (active N 0 0 0 0 0 Nonirritating 136 z ...., lotion) ingredient) § GS (Blemish 3 13.8 (active N 4 0 Minimally irritating 150 < stick) ingredient) -tT1

GS (First 2 5.0 (active N 0 Minimally irritating 149 ~ aid cream) ingredient)

GS 3 2.0 (active N 0 0 0 0 0 0 Nonirritating 136 (Protective ingredient) cream)


> [/) [/)

til [/) [/)

a: GS/SEb 6 100 N 0 0 0 Nonirritating 158 til z GS/SE 9 50 y 67 0 0 0 0 0 Minimally irritating 135 :-:l GS/SE 3 5.0 in water N 0 0 0 0 0 0 Nonirritating 146 0 GS/SE 6 50 in corn oil y 1 1 0 0 0 Minimally irritating 137 r GS/SE 6 50 in corn oil N 1 1 0 0 0 Minimally irritating 137 -<

(j

GS/SE 6 50 in corn oil N 1 1 0 0 0 Minimally irritating 137 til :;Q

GS 6 100 N 0 Nonirritating 137 -< GS 6 100 N 6 2 1 1 0 Slightly irritating 137 r

[/)

GS 6 100 N 5 2 1 0 Minimally irritating 137 -l GS 6 100 N 7 2 0 Slightly irritating 137 til

> GS 6 100 N 4 2 1 0 Mildly irritating 137 :;Q - GS 6 100 N 1 0 Nonirritating 137 > 00 -l ...., GS 6 100 N 3 2 0 Mildly irritating 137 til

GS 6 100 N 2 2 0 Mildly irritating 148 > GS 6 100 N 1 1 0 Minimally irritating 148 z

0 GS 6 100 N 2 1 0 Minimally irritating 148 0 GS 6 100 N 1 1 0 Minimally irritating 137 r GS 6 50 in corn oil N 2 0 Minimally irritating 137 -<

(j til

"Glyceryl Stearate :;Q -<

bGlyceryl Stearate/SE r Y =Yes [/)

-l N =No til

> :;Q > -l til ' [/) til



12.50"/o Glyceryl Stearate on seven males and females. The test material was applied under occlusion to the back of each subject for 24 h; upon patch removal, sites were scored and a fresh patch applied. This procedure was repeated daily for 21 days. Although it produced minimal or definite erythema in five subjects, the product containing 12.5ll!o Glyceryl Stearate was considered to be "essentially nonirritating," when compared to positive and negative control values. <1601

Repeated Insult Patch Test (RIPT) A RIPT was used on 61 subjects to evaluate the potential irritancy and sensitizing effect of 20ll!o

Glyceryl Stearate in a 10ll!o mineral oil/10 percent petrolatum vehicle. Ten to fifteen 24-hour occlusive patches were applied for two to three weeks. After a 10- to 14-day rest, a challenge patch was applied to either the original or a virgin site; the sites were scored on patch removal. Twenty percent Glyceryl Stearate did not induce sensitization.< 1371

Patches containing 20ll!o Glyceryl Stearate in petrolatum were applied daily for three days to the arms of 1206 subjects; the Chamber method was used. None of the subjects developed allergic reactions. 11611

A suntan lotion and a face cream, each containing 2.0ll!o Glyceryl Stearate, were tested with a RIPT. Ten occlusive 24-hour patches containing the test substance were applied to one arm of each of 19 subjects for two weeks. Patch sites were scored 24 hours after each patch was removed, before a fresh patch was reapplied. Ten to 14 days after the removal of the tenth induction patch, 24-hour challenge patches were applied to each original site as well as to a virgin site. Sites were scored 24 and 48 h later. There were no reactions to either induction or challenge patches and it was concluded that the suntan lotion and the face cream are incapable of inducing significant irritation or sensitization.< 1611

A similar RIPT was used to evaluate a first aid cream containing 5.0ll!o Glyceryl Stearate. Occlusive patches with the test product were applied for 24 h to subject's skin once daily for two to three weeks. After a 10- to 14-day rest, a single occlusive 24-hour challenge patch was applied. Thirtyone of the 52 subjects tested experienced minimal irritation to the induction patches but none had a sensitization reaction to the challenge patch. <147

•149

1

The same first aid cream was tested for cumulative irritancy in a Maibach 21-day Cumulative Irritancy Test. Occlusive patches containing the test product were applied to the backs of nine subjects. The patches were removed 24 h later, the sites scored, and fresh patches reapplied to the site. This procedure was repeated until21 patches had been applied. The cumulative irritation index for this formulation was calculated to be 48 (maximum score = 756). <1491

Photoallergy and Phototoxicity A suntan lotion and a face cream, each containing 2ll!o Glyceryl Stearate, were tested for potential

ph ototoxicity and photoallergenicity. For the phototoxicity test, 0.2 ml of the lotion was tested under occlusive patches to a tape-stripped area of each arm of the subject. The patches were removed 24 h later and the sites scored for irritation. The contact site of the left arm was designated as the nonirradiated control and that of the right arm was exposed to four FYBL black lights (maximum output = 360 nm) at a dose of 4400 p.W lcm2 for 15 min at a distance of 10-12 em. Immediately after irradiation and after 24, 48, and 168 h, none of the ten subjects showed reactions, either at control or irradiated sites. It was concluded that the two formulations are nonphototoxic. 11611

For the photoallergy test, the protocol was similar to that used above except that patches were applied and the sites irradiated every other day until ten patches had been applied. After a two-week rest, 24-hour challenge patches were applied to the original and to virgin sites. The treated sites were scored upon patch removal and then they were irradiated. Treated sites were again scored at 24, 48, and 72 h after irradiation. Occasional irritation occurred at various sites but both products were considered to be "incapable of producing significant photoallergy'' in humans.< 1611

Other Clinical Experience Rudzki et al. <1631 added various emulsifiers to a base containing a known irritant to determine if

the emulsifiers enhanced percutaneous absorption. Patches containing various concentrations of potassium dichromate in a white paraffin base were applied to the arms of 66 men and women. When 10ll!o Glyceryl Stearate was added to each patch, subjects reacted to lower dichromate concen-

184



trations. An in vitro study showed that 100?o Glyceryl Stearate enhanced release of Cr(VI) from the white paraffin base.

Worker Experience A chemical manufacturing company which has been producing Glyceryl Stearate and Glyceryl

Stearate/SE for 14 years has no complaints of adverse reaction from any employee directly involved with the handling of these ingredients."••>

SUMMARY

Glyceryl Stearate and Glyceryl Stearate/SE are the esterification products of glycerine and stearic acid. Glyceryl Stearate/SE contains excess stearic acid reacted with potassium hydroxide to produce a self-emulsifying product. Both Glyceryl Stearate and Glyceryl Stearate/SE are white to creamcolored wax-like solids. Either ingredient may contain mono-, di-, and triglyceride impurities and fatty acid impurities.

Glyceryl Stearate and Glyceryl Stearate/SE are widely used in cosmetic formulations as emollients, auxiliary emulsifiers, viscosifiers, stabilizers, bases, and surfactants. Glyceryl Stearate is used in more than 1200 cosmetic formulations at concentrations of ::::0.1-500?o; Glyceryl Stearate/ SE is used in over 200 cosmetic products at concentrations of ::::0.1-500?o.

Glyceryl Stearate is also widely used in foods as a surfactant, emulsifier, and thickener. Glyceryl Stearate is an antistalant and dough conditioner in breads and is also used in pharmaceutical bases. Glyceryl Stearate has been granted regulatory status as GRAS ingredient, an indirect food additive, a direct food additive, and as an OTC substance.

In acute oral toxicity studies in rats, Glyceryl Stearate and Glyceryl Stearate/SE were nontoxic or mildly toxic. In chronic studies, 15-250?o Glyceryl Stearate in the diet of rats for three consecutive generations had no adverse effects. Rats fed a diet containing 250?o Glyceryl Stearate for two years developed renal calcifications.

Glyceryl Stearate and Glyceryl Stearate/SE at concentrations of up to lOOO?o were reported to be mildly irritating or nonirritating to the skin of rabbits. In subchronic and chronic dermal toxicity tests, 4-50?o Glyceryl Stearate was nontoxic to rabbits but did cause moderate irritation (slight to moderate erythema, edema, atonia, desquamation, and/or fissuring). In seven guinea pig sensitization studies, it was concluded that neither Glyceryl Stearate nor Glyceryl Stearate/SE was capable of inducing sensitization.

In primary eye irritation studies, Glyceryl Stearate and Glyceryl Stearate/SE at concentrations up to 1000?o were mildly irritating or nonirritating when instilled in the eyes of rabbits.

Glyceryl Stearate, fed to mice in doses of 50-100 mg/day or 1.50?o in the diet until they died, did not induce significant brain or gastric tumor formation, respectively. Five percent Glyceryl Stearate did not promote the carcinogenicity of DMBA in mouse skin.

Single and Repeated Insult Patch Tests used to evaluate human skin irritation and sensitization potential of Glyceryl Stearate and Glyceryl Stearate/SE showed both ingredients to be nonse~''itizing and nonirritating. Products containing 20?o Glyceryl Stearate were nonphototoxic anu .tonphotoallergic. Worker experience shows that Glyceryl Stearate and Glyceryl Stearate/SE are nonirritating to human skin.

DISCUSSION

Glyceryl Stearates are used in 1,400 cosmetic formulations to regulate their thixotropic indices and viscosity. The viscosity of the emulsions containing these compounds is directly proportional to the amount of Glyceryl Stearates present. Thus, products that contain up to 30?o are lotions and those containing lOO?o are creams.

In food products, Glyceryl Stearates are used as antistalants, surfactants, emulsifiers, flavor dispersants, antisticking, and thickening agents. They are GRAS ingredients and have been approved as direct food additives by the Food, Drug and Cosmetic Act. The compounds have also

185



been used in pharmaceutical preparations for about 40 years. In pharmaceuticals they are largely used as solidifiers and controlled release agents. They are also used in suppositories. It is not surprising, therefore, to find extensive literature on the preparation, usefulness, and safety of these ingredients. There are, in addition, numerous unpublished data on animal tests applicable to the assessment of the safety of these ingredients.

Glyceryl Stearates have been subjected to a number of chronic toxicity tests that show no adverse effects on reproduction in rats fed high levels in the diet through three generations, 110

> no tumor initiation1152

·'5 '> and no tumor promotion in mice."54>

Clinical safety data are limited, but long clinical experience and abundant animal studies prove these compounds to be nonsensitizing, nonphototoxic and nonphotosensitizing. Human phototesting, single and repeated patch testing has been carried out on too few subjects, but none of the available data provides suspicion of risk associated with the use of Glyceryl Stearate and Glyceryl Stearate/SE as cosmetic ingredients. Furthermore, chemical manufacturing worker experience for 14 years has produced no adverse employee reactions.

CONCLUSION

On the basis of the available animal data and clinical experience presented in this report, the Panel concludes that Glyceryl Stearate and Glyceryl Stearate/SE are safe for topical application to humans in the present practices of use and concentration.

ACKNOWLEDGMENT

Mr. Kevin Fisher, Scientific Analyst and writer, prepared the literature review and technical analysis used by the Expert Panel in developing this report.

REFERENCES

I. ESTRIN, N.F. (ed.). (1977). CTFA Cosmetic Ingredient Dictionary, 2nd ed. Washington, DC: Cosmetic, Toiletry and Fragrance Assoc.

2. CRESSEY, S. (1957). Glyceryl monostearate in food. Food Manuf. 32, 165-8, 175. 3. COSMETIC, TOILETRY and FRAGRANCE ASSOCIATION (CTFA). (1974). CTFA Standards:

Cosmetic Ingredient Descriptions. Washington, DC. 4. VERKADE, P .E. and VAN DER LEE, J. (1936). The synthesis of glycerides with the help of trityl com

pounds. II. Diaciddiglycerides Rec. Trav. Chim. 55, 267-77. 5. BERTONI, M.H., RATSZTEOM DE GYMERYNG, F., and CATTANEO, P. (1963). Studies on

monoglycerides. I. Preparation of pure monoglycerides of saturated fatty acids. Methods of determination. Rev. Arg. Grasas Aceites (591), 3-12.

6. VEIKHERTZ, I. (1932). Preparation of glycerol mono- and distearates. Khim. Farm. Prom. 284-6. 7. LICHNEROVA, I. (1970). Properties of glycerol esters of higher fatty acids studied as auxiliary

substances for rectal administration. Acta Fac. Pharm. 70(18), 117-67. 8. MAJOR, F. and PEARMAN, R.W. (1948). Shark liver oil from Trinidad. Bull. Imperial Inst. (4691),

53-6. 9. MERAT, P. (1949). Hydrogenated whale oil. Its industrial uses. Oleagineux 4(4), 203-12.

10. SEGALAS, L. (1971). Use and toxicity of glyceryl monostearate in bakery products. Afinidad 28(288), 735-8.

II. HAWLEY, G.G. (ed.). (1971). The Condensed Chemical Dictionary, 8th ed. New York: Van Nostrand Reinhold.

12. WINDHOLZ, M. (ed.). (1976). The Merck Index, 9th ed. Rahway, NJ: Merck and Co. 13. CORNISH, R.M. (1968). Glyceryl monostearate. J. Soc. Cosmet. Chern. 19, 109-17. 14. MALKIN, T. and EL SHURBAGY, M.R. (1936). X-ray and thermal examination of the glycerides. J.

Chern. Soc. 1628-34.

*Available upon request: Administrator, Cosmetic Ingredient Review, Suite 810, 1110 Vermont Ave., NW, Washington, DC 20005.

186



15. MORRISON, R.T. and BOYD, R.N. (1973). Organic Chemistry, 3rd ed. New York: Allyn and Bacon, Inc.

16. SENZEL, A.J. (ed.). (1977). Analysis of thiglycolate hair straightener creams. Newburger's Man. Cosmet. Anal., 2nd ed., p. 85.

17. YANISHLIEVA, N. and POPOV, A. (1971). Effect of hydroxy compounds on the autoxidation of unsaturated fatty acid methyl esters in the initial stage of the process. Izv. Otd. Khim. Nauki, Bulg. Akad. Nauk. 4(3), 389-400.

18. ARMSTRONG, N.A. (1968). The hydrolysis of monostearin in an acidic medium. J. Soc. Cosmet. Chern. 19(11), 707-11.

19. NOVITSKA Y A, G. V. and VERESHCHAGIN, A. G. (1969). Chromatographic separation of higher fatty acid monoglycerides to chain and unsaturation. J. Chromatogr. 40(3-4), 422-30.

20. SAHASRABUDHE, M.R. (1%7). Chromatographic analysis of polyglycerols and their fatty acid esters. J. Am. Oil Chern. Soc. 44(7), 376-8.

21. BINDLER, F., LAUGEL, P., and HASSELMANN, M. (1979). Thin-layer chromatography with a flame ionization detector. Possibilities and limits of use of the method in food chemistry. Dtsch. Lebensm.-Rundsch. 75(4), 111-8.

22. NEISSNER, R. (1978). Preparation, analysis and TLC separation of partial esters of fatty acids with polyvalent alcohols. Fette, Seifen, Anstrichm. 80(8), 303-11.

23. SINSEL, J.A., LARUE, B.M., and MCGRAW, L.D. (1975). High-pressure liquid chromatographic analysis of glyceride-base lubricants. Anal. Chern. 47(12), 1987-93.

24. SUCKER, H. (1964). Qualitative analysis of salves. IX. Adsorption chromatographic separation of emulsifiers. Arch. Pharm. 297(9), 543-6.

25. WEKELL, J.C., HOULE, C.R., and MALINS, D.C. (1964). A method for the isolation of mono- and dihydric alcohols from complex mixtures. J. Chromatog. 14(3), 529-31.

26. GOLUB, A.I. and PETROVA, L.M. (1972). Gas-chromatographic determination of stearin in phenolformaldehyde resins. Khim. Prom. 48(6), 470-1.

27. SUFFIS, R., SULLIVAN, T.J., and HENDERSON, W.S. (1965). Identification of surface active agents as trimethylsilyl ether derivatives by gas chromatography. J. Soc. Cosmet. Chern. 16(13), 783-94.

28. WEAST, R.D. (ed.). (1978). CRC Handbook of Chemistry and Physics, 59th ed. West Palm Beach, Florida: CRC Press.

29. SCHWARTZBERG, S. (1961). Allergic eczematous contact dermatitis caused by sensitization to glyceryl monostearate. Ann. Allergy 19(4), 402-3.

30. GOLDSMITH, H.A. (1943). Nonionic surface-active agents display unique characteristics. Chern. Ind. 52, 326-8.

31. BALSAM, M.S. (ed.). (1972). Cosmetics: Science and Technology, 2nd ed. New York: lnterscience Publishers.

32. NEWBURGER, S.H. (1947). Analysis of a sunburn-preventive cream. J. Assoc. Offic. Agr. Chern. 30, 683-90.

33. GUERNET, M., ESPINASSOU, E., and HAMON, M. (1973). Periodimetric assay in nonaqueous medium. Ann. Pharm. Fr. 31, 343-8.

34. VAN GORKOM, M., VANDER MOLEN, M.H., and KORVER, 0. (1975). ESR study of aqueous dispersions of beta-lactoglobulin and spin-labelled glyceryl monostearate. Biochim. Biophys. Acta 392(1), 141-7.

35. NOLL, H. and JACKIM, E. (1958). The chemistry of the native constituents of the acetone-soluble fat of Mycobacterium tuberculosis (Brevannes). I. Glycerides and phosphoglycolipides. J. Bioi. Chern. 232(2), 903-17.

36. CHESHKO, F.F. and SHVAIKA, T.N. (1971). Synthesis and identification of some mono- and dicarboxylic acid esters. Zh. Prikl. Khim. 44(5), 1107-16.

37. FORMAN, B.J. and GRADY, L.T. (1969). Inclusion compounds in pharmaceutical analysis. I. Determination of dienestrol in dienestrol cream. J. Pharm. Sci. 58, 1262-5.

38. BEHR, M. and KASSEBAUM, H. (1977). Studies on the release rate of salicylic acid from ointment layers. 1. Hydrocarbon mixtures. Fette Seifen Anstrichm. 79(11), 460-4.

39. CODE OF FEDERAL REGULATIONS (CFR). (1979). 21 CFR 121.101. 40. ATHERTON, J.G. and MAXCY, W.J. (1967). Effect of composition variations of glycerol esters on the

physical properties of cosmetic emulsions. Proc. Sci. Sect. Toilet. Goods Assoc. 46, 39-43. 41. ATHERTON, J.G. and MAXCY, W.J. (1967). Glycerol esters in cosmetic emulsions. Drug Cosmet. Ind.

100(3), 50, 52, 54, 16206.

187



42. IDSON, B. (1974). Nonionic skin lotions. Cosmet. Perfum. 89, 59-61. 43. BOBBE, D., MATHIS, C., METZINGER, P., and GABLER, W. (1976). Oil suspensions for soft cap

sules. Rheological study of mixtures of fat excipients. Labo-Pharma-Probl. Tech. 24(256), 651-61. 44. RUTKOWSKI, A. and ELSNER, Z. (1973). Rheological properties of lipophilic bases applied to

cosmetics. Cosmet. Perfum. 88, 23-6. 45. EROS, I. and UGRI-HUNYADVARI, E. (1977). Theoretical and practical questions of the structure

rheological research of ointments. Part 2. Effect of surface active components on the rheological properties. Pharmazie 32(1 I), 731-6.

46. STEJSKAL, J. and UYHNANEK, K. (1957). The effect of the composition of wool-fat alcohols upon the stability of the emulsion forms in wool-fat alcohol ointments. Parfum. Kosmet. 38, 566-67.

47. GOLUCKI, Z. (1966). a-Tocopherol acetate as stabilizer for ointment bases. Farm. Pol. 22(5), 333-7. 48. FIERO, G.W. and DUTCHER, M.W. (1945). Glycol esters in ointment bases. J. Am. Pharm. Assoc. 34,

56-9. 49. CATLAINE, E.L. (1945). Washable ointment bases. Bull. Am. Soc. Hosp. Pharmacists 2, 32-3, 58. 50. MILJEVIC, D. and DANILOVIC, M. (1977). Possibility of using glycerin monostearate for hydrophylic

ointments. Arch. Farm. (2792), 95-8. 51. FOOD and DRUG ADMINISTRATION (FDA). (Aug. 31, 1976). Product Formulation Data. Computer

Printout. Washington, DC. 52. LANG, M., FORMENT, R., and DUNKLEY, W.L. (1976). Influence of composition and processing on

sensory properties of nonfat milk. J. Dairy Sci. 59(9), 1560-7. 53. BARRETT, F.F. (1970). New developments in multifunctional dough conditioners. Baker's Dig. 44(1),

66-8. 54. BRADLEY, W.B., GASE, W.T., and LUCKA, L.O. (1948). Bread softeners. Open forum. Proc. Am.

Soc. Bakery Eng. 24, 53-63. 55. COPPOCK, J.B.M. (1950). Some remarks on the American baking industry. Food 19(220), 14. 56. COPPOCK, J.B.M. (1954). Science and baker. Chern. Ind. 1954(43), 1306-11. 57. EDELMANN, E.C., CATHCART, W.H., and BERQUIST, C.B. (1950). The effect of various ingre

dients on the rate of firming of bread crumb in the presence of polyoxyethylene (mono) stearate and glyceryl monostearate. Cereal Chern. 27(1), 1-14.

58. HART, M.R., GRAHAM, R.P., GEE, M., and MORGAN, JR., A.I. (1970). Bread from sorghum and barley flours. J. Food Sci. 35(5), 661-5.

59. HUSSAIN, M. and SATTI, M-U-H. (1970). Development of long-life roti bread. Pakistan J. Sci. Ind. Res. (1294), 408-10.

60. JAIN, S. and SHERMAN, P. (1976). The influence on bread texture of partially replacing wheat with potato products. J. Texture Stud. 7(3), 297-311.

61. JONGH, G. (1961). The formation of dough and bread structures. I. The ability of starch to form structures, and the improving effect of glyceryl monostearate. Cereal Chern. (3892), 140-52.

62. JONGH, G., SLIM, T., and GREVE, H. (1968). Bread without gluten starch dough glyceryl monostearate. Baker's Dig. 42(3), 24-9.

63. KIM, H.-S. and LEE, H.-J. (1977). Development of composite flours and their products utilizing domestic raw materials. Part IV. Effect of additives on the bread-making quality with composite flours. Hanguk Sikpum Kwahakhoe Chi 9(2), 106-15.

64. FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY (FASEB). (1976). Evaluation of the Health Aspects of Glyceryl Stearate.

65. RUBBO, S.D. and DAVEY, M.E. (1945). Some laboratory findings pertaining to the clinical use of penicillin. Med. J. Australia 32(25), 449-53.

66. MEZEY, G. (1971). Effect of lipophilic emulsifiers on drug release from suppositories made with cocoa butter. Pharmazie 26(3), 166-9.

67. KEDVESSY, G. and REGDON, G. (1962). Viscosity of suppository masses. Pharm. Zentralhalle 101, 389-98.

68. REGDON, G. and KEDVESSY, G. (1962). Effect of viscosity of the rat material on the homogeneity of suppositories prepared by a casting method. Gyogyszereszet 6, 452-8.

69. TORRADO-V ALEIRAS, J .J. (1969). Stability of suppositories. Anales Real Acad. Farm. 35(3), 375-92. 70. LICHNEROV A, I. and CHALABALA, M. (1968). Glycerin esters of some higher fatty acids as phar

maceutical auxiliary substances. III. Melting and solidification of binary and ternary systems. Cesk. Farm. 17(6), 279-81.

188



71. LICHNEROVA, I. and CHALABALA, M. (1969). Glycerin esters of some higher fatty acids as pharmaceutical auxiliaries. IV. Rheological properties. Cesk. Farm. 18(8), 369-72.

72. TOROSIAN, G. and LEMBERGER, A.P. (1968). Surface films of soybean lecithin. II. Interactions between lecithin and lipid substances in mixed monomolecular films. J. Pharm. Sci. 57(1), 17-22.

73. TRIVEDI, B.M. and PATEL, R.K. (1970). Stability studies on dermostatin in selected ointment bases. Hindustan Antibiot. Bull. 12(4), 131-7.

74. CONLEY, A.J. and KABARA, J.J. (1973). Antimicrobial action of esters of polyhydric alcohols. Antimicrob. Agents Chemother. 4(5), 501-6.

75. WEDDEBURN, D.L. (1958). Preservation of toilet preparations containing nonionics. J. Soc. Cosmet. Chern. 9, 210-28.

76. PINTER, K.G. and KARLE, I.P. (1966). Effect of ingestion of various mono- and triglycerides on serum triglyceride concentration. Am. J. Clin. Nutr. 18(3), 165-8.

77. GALL, D. (1966). Adjuvant activity of aliphatic nitrogenous bases. Immunology 11(4), 369-86. 78. BLONDER, E., KLIBANSKY, C., and DE VRIES, A. (1976). Effects of detergents and choline

containing phospholipids of human spleen glucocerebrosidase. Biochim. Biophys. Acta. 431(1), 45-53. 79. BORNSCHEIN, M., VOIGHT, R., and PETRI, U. (1978). Effect of particle glycerides on the release of

aminophenazone from suppositories. Pharmazie 33(9), 591-3. 80. ELSNER, Z., KROWCZYNSKI, L., and LESZCZYNSKA-BAKAL, H. (1966). Effect of some viscosity

increasing substances on the suppository base Lasupol G. Pharmazie 21(12), 761-5. 81. GYARMATI, L., RACZ, I., CSONTOS, A., and SA TORY, E. (1972). Examination of Halidorfumarats

release from suppositories. Acta Pharm. Hung. 42(6), 278-85. 82. FUCHS, P., SCHOTKY, E., and SCHENCK, G. (1970). Effect of surface-active agents as lubricants for

tablets on the release of active substance from compressed pharmaceutical products. Pharm. Ind. 32(7), 581-3.

83. EROS, I., and HUNYADVARI, E. (1972). Effect of some water/oil emulsifiers on the structural rheological properties of salves. Sci. Pharm. 40(1), 28-35.

84. SZEL, M. and REGDON, G. (1977). Biopharmaceutical investigation of suppositories containing phenazone. Part 1. Description of the investigation methods and study of physical parameters of the suppositories. Gyogyszereszet 21(10), 370-4.

85. SZEL, M. and REGDON, G. (1978). Biopharmaceutical investigation of suppositories containing phenazone. Part 1. Description of the investigation methods and study of physical parameters of the suppositories. Gyogyszereszet 22(2), 51-4.

86. GAIDENKO, M.V., NAZAROV, N.I., KALOSHINA, E.N., and TSIVTSIVADZE, G.V. (1975). Effect of surfactants on the drying of macaroni. Khlebopek. Kondieter. Prom-st. 6, 29-31.

87. KALININA, M.A., FILINA, N.D., NAZAROV, N.l., GAIDENKO, M.V., LEKHTER, A.E., and MINAEV A, S. V. ( 1976). Effect of surfactants on macaroni extrusion. Khlebopek. Konditer. Prom-st. 7, 33-4.

88. NAZAROV, N.I., EGOROVA, N.I., and KONDRATENKO, S.S. (1972). Effect of surface-active agents on the amount of carotenoids in macaroni products. Khlebopek. Konditer. Prom. 2, 20.

89. NAZAROV, N.I., GAIDENKO, M.V., LEKHTER, A.E., and OBYAKOVA, G.S. (1975). Surfactants to improve macaroni products. Khlebopek. Konditer. Prom.-st. 4, 27-8.

90. NAZAROV, N.I., GAIDENKO, M.V., KALININA, M.A., NECHAEV, A.P., BASKAEVA, A.E., and MALOFEEVA, L.S. (1973). Effect of surface-active substances on mechanical-structural characteristics of macaroni dough. Khlebopek. Konditer. Prom. 3, 23-4.

91. GORRILL, A.D.L. and NICHOLSON, J.W.G. (1972). Use of the Willems polytron to homogenize fat and disperse insoluble ingredients in high fat liquid milk replacers. Can. J. Anim. Sci. 52(3), 477-84.

92. MICKLE, J.B., SMITH, W., TIETZ, J.M., TITUS, T.C., and JOHNSTON, M. (1971). Influence of emulsifier type and solubility on the stability of milk fat-water emulsions. J. Food Sci. (3693), 423-5.

93. KAPAS, M., REGDON, E., and REGDON, G. (1979). Effect of adjuvants on the physical properties and release from suppositories containing salicylic acid derivative>. Part 2. Measurement of in vitro drug release by membrane diffusion method. Acta Pharm. Techno!. 25(2), 109-18.

94. REGDON, E., KAPAS, M., and REGDON, G. (1979). Effect of adjuvants on the physical properties and release from suppositories containing salicylic acid derivatives. Part 1: Experimental methods and physical parameters of suppositories. Acta Pharm. Techno!. 25(2), 101-8.

95. PARROTT, E.L. (1971). Salicylate absorption from rectal suppositories. J. Pharm. Sci. 60,867-72. 96. REGDON, G., REGDON, E., and KAROLY!, I. (1976). Acetylsalicylic acid-containing suppositories.

189



The effect of viscosity-increasing additives on the physical and chemical stability. Dtsch. Apoth.-Ztg. 116(35), 1280-2.

97. GORYACHEVA, A.F., SEMENOVA, V.A., SHKVARKINA, T.I., LEKHTER, A.E., CHERNSHEVA, D.A., OBY AKOVA, G.S., and SHUKSHINA, T.F. (1973). Improving bread quality by use of surfactants. Khlebopek. Konditer. Prom. 5, 9-11.

98. EDELMANN, E.C. and CATHCART, W.H. (1949). Effect of surface-active agents on the softness and rate of staling of bread. Cereal Chern. 26(4), 345-57.

99. GOYAL, O.K. and SRINIVASAN, M.R. (1973). Quality of soft-serve ice cream as influenced by the levels of fat, emulsifier, sucrose substitutes and processing conditions. J. Food Sci. Techno!. 10(3), 122-4.

100. NIELSEN, B.J. (1976). Function and evaluation of emulsifiers in ice cream and whippable emulsions. Gordian 76(7-8), 220, 222-5.

101. ZUBER, M., CHEMTOB, C., and CHAUMEIL, J.C. (1979). Availability from dermic forms. III. Comparative study of emulsified ointments (oil/water). Use of a cell with a cellulose acetate-based membrane. Sci. Tech. Pharrn. 8(1), 47-52.

102. MIKHAILOV, V.S., DOROZHINA, T.P., and DZHAFAROVA, R.I. (1974). Effect of fats with various surfactants on cake quality. Khlebopek. Konditer. Prom-st. 8, 22-4.

103. GREEN, M. (1946). Some pharmaceutical necessities newly admitted to National Formulary. J. Am. Pharrn. Assoc. Prac. Pharrn. Ed. 7(7), 297-303.

104. SAVOSTIKOVA, N.F., LUKYANOV, A.B., BERKENGEIM, B.M., and TATARNIKOVA, N.P. (1972). Starch treated with glycerol rnonostearate as an effective emulsifier for cosmetic creams. MasloZhir. Prom. 38(4), 21-2.

105. ZAKRZEWSKI, Z. and PIETURA, A. (1976). Study of the effect of adjuvants on the release of oxytetracycline from ointments. Farm Pol. 32(4), 287-91.

106. OORAIKUL, B. and HADZIYEV, D. (1974). Effects of surfactants, freezing, and thawing on starch and pectic substances in the production of dehydrated mashed potatoes. Can. Inst. Food Sci. Techno!. J. 7(3), 213-9.

107. CHRISTENSEN, E.V. (1%0). An emulsified cream for dental use. Arch. Pharrn. Chern. 67, 185-7. 108. ZAKRZEWSKI, Z. and PIASECKA, H. (1977). Effect of substrate, particle size, and drug concentration

on drug release from ointments. Farm Pol. 33(3), 137-43. 109. NIIYA, I., KINOSHITA, Y., IMAMURA, M., OKADA, M., and MATSUMOTO, T. (1970). Deteriora

tion of oils and fats of the hardened coconut oil series. 7. Deterioration prevention by the addition of surfactants. Yakagaku 19(7), 473-81.

110. HODGE, D.H. (1978). Monoglycerides in cake production. Getrede, Mehl Brot 32(2), 39-43. Ill. KOZMINA, E.P., CHEKMAREVA, LB., MIKHAILOV, V.S., and DOROZHKINA, T.P. (1974). Ef

fect of different fat compositions on the quality of plum-cake. Izv. Ucheb. Zaved., Pisch. Tekhnol. 3, 149-50.

112. STARHA, L. and CHALABALA, M. (1971). Peroral drugs with protracted action. V. Relation between the molding pressure and the release of drugs. Cesk. Farm. 20(1), 23-5.

113. MEISNER, D. (1%9). Succinylated rnonoglyceride. Baker's Dig. 43(3), 38-41. 114. KOZMINA, N.P., PLAKHOV, V.I., and FOMENOK, S.K. (1973). Effect of emulsifiers on the proper

ties on the gluten, dough, and quality of bread. Khlebopek. Konditer. Prom. 10, 7-8. 115. SHEKERDZHIISKI, R. and TRANDAFILOV, T. (1972). Effect of additives on the separation of a solid

readily soluble drug from a hydrophobic tablet matrix. Farrnatsiya 22(3), 39-46. 116. SHEKERDZHIISKI, R., TRANDAFILOV, A., and TRABDAFUKIV, T. (1972). Effect of adjuvants on

the escape of slightly soluble drugs from hydrophobic tablet matrix. Pharrnazie 27(3), 167-8. 117. GOLUCKI, Z. (1967). Influence of surface-active substances on the absorption of water by white

petrolatum. Diss. Pharrn. Pharrnacol. 19(4), 413-6. 118. THOREN, I. (1972). Possibilities for emulsifiers in alimentary paste preparation. Ber. Dururn-Teigwaren

Tag. 79-87. 119. MAGGIO, B., and LUCY, J.A. (1976). Polar-group behavior in mixed rnonolayers of phospholipids and

fusogenic lipids. Biochern. J. 155(2), 353-64. 120. GROVES, M.J. and GALINDEZ, F.E. (1976). The effect of environmental conditions on the release of

brornphenirarnine from protein/wax matrix tablets. Acta Pharrn. Suec. (1394), 373-84. 121. ABDEL-RAHMAN, A.-H.Y. (1975). Production of margarine oil from cottonseed oil and corn oil. J. Oil

Techno!. Assoc. India 7(4), 99-100. 122. ALLEN, B.F., and LEVINE, P.J. (1958). Dental lotion. J. Am. Pharrn. Assoc., Pract. Pharrn. Ed. 19,

154-5.

190



123. ORTHOEFER, F.T. (1976). Effect of type of fat on starch pastes containing glycerol monostearate. Cereal Chern. 53(4), 561-5.

124. KASSEM, M.A., SALAMA, H.A., AMMAR, H.O., and EL-RIDY, M.S. (1977). On the dissolution and bioavailability of phenindion. III. Dissolution and bioavailability of phenindione capsules. Pharm. Ind. 39(4), 396-9.

125. NEELAKANTAN, S. and MANIMEGALAI, G. (1978). Studies on peanut butter-a feasibility report and varietal trails. Fats Oil Relat. Food Prod., Their Prep., Symp. 33-7.

126. KASSEM, A.A., EL-GENDY, A.R., and RIFAA T, N.E. (1970). Release of isoprenaline sulfate from certain sublingual tablet bases. Bull. Fac. Pharm., Cairo Univ. 8(1), 161-7.

I27. ARMENGOL, J., GASULL, E., and MARQUES, J. (1974). Contents of mono-, di-, and triglycerides in food emulsions. An. Bromatol. 26(4), 357-89.

128. TENNEY, R.J., and SKILLICORN, A.T. (1972). Comparative effects of sodium stearoyl-2-lactylate and various emulsifiers in simple oil-water emulsions and food systems. Food Prod. Develop. 6(5), 80-2, 84.

129. MISRA, A.L. and PONTANI, R.B. (1978). An improved long-acting delivery system for narcotic antagonists. J. Pharm. Pharmacal. 30(5), 325-6.

130. BUENSOD, M. and FAVARGER, P. (1956). Digestibility of palmitic and stearic acids and their glycerol esters in the rat. Helv. Physiol. Pharmacal. Acta. 14, 299-303.

131. JAMINET, F. and LOUIS, G. (1%8). Effect of some lubricants on the stability of aspirin in compressed tablets. Pharm. Acta Helv. 43(3), 153-7.

132. INOLEX LABS. (1975). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. ID.*

133. INOLEX LABS. (1975). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. IE.*

134. INOLEX LABS. (1975). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. IF.*

135. BIO-TOXICOLOGY LABS (BTL). (1975). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. 2B. *

136. LEBER CO LABS. (1978). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. 6.*

137. AVON PRODUCTS. (1976). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. 3. •

138. HILL TOP RESEARCH. (1968). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. 2C. *

139. INOLEX LABS. (1975). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. !C.*

140. INOLEX LABS. (1975). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. lB.*

141. INOLEX LABS. (1976). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. lA. *

142. HAZEL TON LABS AMERICA. (1977). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. 7. *

143. INTERNATIONAL RESEARCH and DEVELOPMENT. (1977). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. 7. *

144. BTL. (1975). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. 2D. * 145. AVON PRODUCTS. (1980). Submission of data by CTFA. Unpublished safety data on Glyceryl

Stearates, Sec. 3. * 146. LEBERCO LABS. (1976). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates,

Sec. 4. * 147. CTFA. (Nov. 4, 1980). Submission of data. Supplementary Information. Memorandum.* 148. AVON PRODUCTS. (1973). Submission of data by CTFA. Unpublished safety data on Glyceryl

Stearates, Sec. 3. * 149. CTFA. (1978). Submission of data. Unpublished safety data on Glyceryl Stearates, Sec. 6. * 150. CTFA. (1979). Submission of data. Summary of unpublished data on Glyceryl Stearates, Sec. 6.* 151. AVON PRODUCTS. (1977). Submission of data by CTFA. Unpublished safety data on Glyceryl

Stearates, Sec. 3. * 152. SZEPSENWOL, J. (1969). Brain nerve cell tumors in mice on diets supplemented with various lipids.

Pathol. Microbiol. 34(1), 1-9.

191



153. SZEPSENWOL, J. (1978). Gastro-intestinal tumors in mice of three strains maintained on fat-enriched diets. Oncology 35(4), 143-52.

154. SAFFIOTTI, U. and SHUBIK, P. (1963). Studies on promoting action in skin carcinogenesis. Nat!. Cancer Inst. Monogr. 10, 489-507.

155. KATO, A., ANDO, K., SUZUKI, S., TAMURA, G., and ARIMA, K. (1969). Anti-tumor activity of monoglycerides and other esters of fatty acids. J. Antibiot. 22(2), 83-4.

156. LEBERCO LABS. (1976). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. 2C.*

157. LEBERCO LABS. (1977). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. 4.*

158. HILL TOP RESEARCH. (1968). Submission of data by CTFA. Unpublished safety data on Glyceryl Stearates, Sec. 2B. *

159. CTFA. (1979). Submission of data. Summary of unpublished data on Glyceryl Stearates.* 160. CTFA. (1978). Submission of data. Unpublished safety data on Glyceryl Stearates, Supplement.* 161. HANNUKSELA, M., KOUSA, M., and PRIILA, V. (1976). Contact sensitivity to emulsifiers. Contact

Dermatitis 2(4), 201-4. 162. FOOD and DRUG RESEARCH LABS (FDRL). (1978). Submission of data by CTFA. Unpublished safety

data on Glyceryl Stearates, Sec. 6. * 163. RUDZKI, E., ZAKRZEWSKI, Z., PROKOPCZYK, G., and KOZLOWSKA, A. (1976). Application of

emulsifiers for the patch test. I. Patch test with potassium dichromate. Dermatologica 153(6), 333-8. 164. EMERY INDUSTRIES. (1979). Submission of data by CTFA. Unpublished safety data on Glyceryl

Stearates, Sec. 2A. *

192



6

Final Report on the Safety Assessment of Glyceryl Oleate

Glyceryl Oleate, the glyceryl 1-monoester of oleic acid, is used in cosmetic products as an emulsifier at concentrations up to 5%.

Oral administration of a single 13 ml/kg dose of a sunscreen formulation containing 5% Glyceryl Oleate to rats produced no signs of toxicity and no lethality.

A single exposure of undiluted Glyceryl Oleate in animal dermal irritation studies produced only minimal irritation. Daily applicatoins of 25.0% corn oil solution of a formulation containing Glyceryl Oleate for 20 days produced severe dermal irritation in rabbits. In a 4-week dermal toxicity/phototoxicity study, product formulations containing up to 5% Glyceryl Oleate produced slight reversible dermal irritation. Subchronic and chronic toxicity data from studies with animals and humans that were used in the safety assessment of glycerides, glycerol, oleic acid, and sodium oleate are presented.

Minimal to moderate eye irritation was produced by undiluted Glyceryl Oleate in rabbits.

Glyceryl Oleate administration was associated with development of a small number of brain tumors in a two-generation study in mice. Digestive tract tumors were found in mide fed 200 mg/mouse per day Glyceryl Oleate for four-seven generations. The results of these studies were considered equivocal. Doses of 1.5 and 6.0 mg/mouse per day of Glyceryl Oleate in saline increased the survival period of mice with implanted Ehrlich ascites tumors; the higher dose inhibited tumor growth.

Formulations containing 5% Glyceryl Oleate were nonirritating in a human cumulative occlusive patch test and in repeat insult patch testing at 15%. Glyceryl Oleate in formulations is not phototoxic.

It is concluded that Glyceryl Oleate is safe as a cosmetic ingredient in the present practices of use and concentration.

CHEMISTRY

Chemical and Physical Properties

G lyceryl Oleate (CAS 111-03-5; 25496-72-4) is the glyceryl 1-monoester of oleic acid (cis-9-octadecenoic acid). The structural formula of Glyceryl Ole

ate is as follows (I>:

391


392 COSMETIC INGREDIENT REVIEW

0 H

CH 3(CH2)7CH=CH(CH2)7C-OCH 2CHOH I CH20H

Glyceryl Oleate occurs as off-white to yellow flakes or as a soft semisolid .. It is dispersible in water and soluble in acetone, methanol, etha~ol, cottonseed oil, and mineral oil. <2 > Glyceryl Oleate is also known as Monoolem, Glyceryl Mono-oleate, and Glycerol Monooleate. . .

A summary of the properties of Gl~ceryl Oleat~ appears m Table 1. In a?dltion the emulsifying and physicochemical propert1es of several monoglycendes

' d. R . d <J> have been measure 1n a uss1an stu y.

TABLE 1. Chemical and Physical

Properties ''·•·'0'

Glyceryl Oleate

Molecular weight 365.55

Melting point (0 C) 35

Boiling point (°C) 238-240

Density 0.9420

Acid value 5 max

Saponification value 155-170

Iodine value 48-80

Analytical Methods

Gas chromatography has been used to isolate and identify monoglycerides (via comparison with standard retention values). <4 > Several other procedures have been coupled with gas chromatography for the determination of the separated monoglycerides or their hydrolysis products (hydrolysis products of Glyceryl Oleate are glycerol and oleic acids). These methods are nuclear magnetic resonance spectrometry<s> and a battery of spectrophotometric analyses. The most widely used chemical assay for the quantitation of glycerol or its 1-monoglycerides involves periodate or lead tetraacetate oxidation of these compounds' primary alcohol groups. <6

·7 > Qualitative chemical tests to assay for the presence

of glycerol involve formation of colored derivatives. <4•6 > Infrared spectrometry

may also be used for functional group identification or for fingerprinting upon comparison with stock standards. <4 >


ASSESSMENT: GLYCERYL OLEATE 393

Method of Manufacture

"Monoglycerides do not occur naturally in appreciable quantities, except in fats and oils that have undergone partial hydrolysis."< 7

l The most important method of monoglyceride preparation is the glycerolysis of fats and oils. Depending on the molar ratios of the reactants, this transesterification reaction can yield product mixtures containing varying quantities of monoglycerides, commercially noted as "40 percent monos" and "60 percent monos."< 7

,

Separation of the monoglycerides from di- and triglycerides is usually achieved by molecular distillation of the glycerolysis product mixture, resulting in the "90 percent mono" mixture used by the cosmetic industry. These commercial 90% monoglyceride mixtures predominantly consist of a-monoglycerides; {3-monoglycerides are present in smaller quantities. Isomerization of {3-monoglycerides to the more stable a-isomers occurs readily. <7

,

The Glyceryl Oleate used by the cosmetic industry may be manufactured by the glycerolysis (glycerol is normally obtained from the triglycerides of oil and fats)< 8 l of oils containing high concentrations of oleic acid: olive oil (80% oleic acid), peanut oil (60% oleic acid), teaseed oil (85% oleic acid), or pecan oil (85% oleic acid). The Glyceryl Oleate could then be distilled from the resulting product mixture (vapor pressure of Glyceryl Oleate at 186°C is 0.2 mm). <7

,

Impurities

Glyceryl Oleate used by the cosmetic industry is a mixture of monoglycerides consisting mainly of the compound, glyceryl a-monooleate. <2

, The stated 90% minimum monoester content as written includes both a- and {3-monoglycerides of oleic acid and glycerol and may also include glycerol monoesters containing other fatty acids depending on the method of manufacture (e.g., sources of reactants).

Constituents, such as free fatty acids and glycerol, may also exist in the Glyceryl Oleate preparation at maximal concentrations of 2.5% and 1.0%, respectively. <2

,

USE

Purpose, Scope, and Extent of Use in Cosmetics

Glyceryl Oleate is used primarily as an emulsifier in cosmetic products. It has been reported to the Food and Drug Administration (FDA) that Glyceryl Oleate is an ingredient in 716 cosmetic formulations. Reported concentrations ranged from ::50.1% to 5%. The concentrations of Glyceryl Oleate in 455 of the 716 cosmetic formulations were not reported to FDA. Cosmetic formulations containing Glyceryl Oleate are predominantly lipsticks, eye shadows, makeup bases, and skin care preparations. <11

,

The cosmetic product formulation listing that is made available by FDA is compiled through voluntary filing of such data in accordance with Title 21 part 720.4 of the Code of Federal Regulations. <l2J Ingredients are listed in preset concentration ranges under specific product type categories. Since certain cosmetic



ingredients are supplied by the manufacturer at less than 100% concentration, the value reported by the cosmetic formulator may not necessarily reflect the actual concentration found in the finished product; the actual concentration in such a case would be a fraction of that reported to the FDA. Data submitted within the framework of preset concentration ranges provide the opportunity for overestimation of the actual concentration of an ingredient in a particular product. An entry at the lowest end of a concentration range is considered the same as one entered at the highest end of that range, thus introducing the possibility of a two- to ten-fold error in the assumed ingredient concentration. See Table 2 for a list of cosmetic products containing Glyceryl Oleate.

Surfaces, Frequency, and Duration of Contact

Cosmetics containing these ingredients are applied to all areas of the skin and mucous membranes. These cosmetics are frequently applied to the face and have the potential for contacting the eye or being ingested from the lips. Products containing these ingredients are applied up to several times a day and can remain in contact with the skin for long periods of time.

Noncosmetic Use

Monoglycerides consisting of a mixture of glyceryl mono- and diesters, and minor amounts of triesters, that are prepared from fats or oils or fat-forming acids derived from edible sources<•J> are affirmed as generally recognized as safe (GRAS) substances (21 CFR 182.4505, 182.90)' 12> and indirect food additives (21 CFR 175.105, 176.210)' 12> for human consumption without restriction on their concentration (at concentrations not to exceed good manufacturing practice, GMP). Federal regulations allow the use of Glyceryl Oleate as a prior-sanctioned food ingredient (21 CFR 181.27)(12 > and as both an indirect (21 CFR 175.300, 175.320)' 12> and direct (21 CFR 172.515)(12 > food additive. These regulatory decisions were based on a review of data in the following areas: subchronic(14

-16>

and chronic (multigeneration reproduction)' 17> feeding studies using Glyceryl Oleate or monoglyceride mixtures derived from oils; subchronic(ls.•9 > and chronic' 20> feeding studies of similar glycerides; studies on the absorption and storage of Glyceryl Oleate and other monoglycerides(l 7

.18

'21 >; and the well-docu

mented metabolic fate of glycerides in the human body. Studies on the metabolites of Glyceryl Oleate, glycerol, and oleic acid as they appear in reviews used by the FDA in the regulation of glycerol, glycerides, and oleic acid are summarized in this report.

The FDA proposed affirmation of GRAS status of Glyceryl Oleate (Proposed issuance of 21 CFR 184.1323) and monoglycerides (proposed issuance of 21 CFR 184.1505) for several additional purposes in human food and concurrent deletion of its listing as a direct food additive (amendment of 21 CFR 172.515).'22 > The listing of the most prevalent fatty acids occurring in monoglycerides in Section 184.1505 included oleic acidY3 >

Glyceryl Oleate is used by the pharmaceutical industry as a carrier compound, ' 23 > in mixed micellar form with bile salts for the enhancement of intestinal drug absorption, ' 24> and for the encapsulation and/or solubilization of partie-


TABLE 2. Product Formulation Data<"l > Ill Ill m

No. of product formulations within each concentration range (%) Ill Ill

Total no. of Total no. ~ formulations containing Unreported m z

Product category in category ingredient concentration >25-50 > 10-25 >5-10 >1-5 >0.1-1 ~0.1 :-:4 C'l

Glyceryl Oleate r--< ("")

Baby lotions, oils, powders, and 56 3 3 m ;:Ia

creams -< Other bath preparations

r-132 0

Eye shadow 2582 26 15 10 r-m

Mascara 397 3 3 > -t

Other eye makeup preparations 230 2 1 m

Hair conditioners 478 5 3 2 Hair shampoos (noncoloring) 909 2 1 Tonics, dressings, and other hair 290

grooming aids Blushers (all types) 819 9 8 Makeup foundations 740 8 8 Lipstick 3319 570 355 215 Makeup bases 831 25 24 Rouges 211 2 2 Other makeup preparations (not eye) 530 7 7 Skin cleansing preparations (cold 680 8 5 1 creams, lotions, liquids, and pads)

Face, body, and hand skin care prep- 832 12 9 2 arations (excluding shaving prepa-rations)

Hormone skin care preparations 10 Moisturizing skin care preparations 747 14 7 3 3 Night skin care preparations 219 5 2 2 Paste masks (mud packs) 171 Wrinkle smoothers (removers) 38 Suntan gels, creams, and liquids 164 7 7 Other suntan preparations 28 3 3

1981 TOTAlS 716 455 0 0 0 18 10 233 IN ~ In



ular drugs. c25-27) Glyceryl Oleate is often used in controlled studies on the phys

iology and biophysics of laboratory-constructed lipid membranes. (lS> The use of Glyceryl Oleate as a fusogen in heterokaryon formation is reported for the study of cell differentiation and genetics. c29

>

BIOLOGY

Absorption, Distribution, and Metabolism

Monoglycerides are metabolized by the same mechanisms as are the triglycerides of the diet. c3 o> Their digestion, intestinal absorption, and transport have been reviewed. c31

-37

>

The catabolic fate of the glycerol and fatty acid components of glycerides is well documented. c35

·37

-39

> Glycerol, phosphorylated and oxidized, enters the glycolytic pathway as dihydroxyacetone phosphate, and fatty acids primarily undergo {3-oxidative degradation to form acetyi-CoA.

Oleic acid, a monoenoic acid, requires an isomerase after partial cleavage to catalyze the isomerization and shifting of the cis double bond before {3-oxidation continues. Oleic Acid is currently being reviewed by Cosmetic Ingredient Review. c4 o>

The monoglyceride, Glyceryl Oleate, as well as its components, glycerol and oleic acid, are common intermediates in both lipid oxidation and synthesis.

General Effects

Addition of 1 mM Glyceryl Oleate plus 3 mM oleic acid to an incubation of the conjugated bile salt, sodium taurodeoxycholate, with segments of everted jejunal intestine from Sprague-Dawley rats diminished the tissue's permeability observed with the bile salt alone. c41

> The mixture also prevented changes in the gross appearance of the intestinal mucosa that were found with the bile salt alone.

Weanling rats were fed a diet of 25% tristearin supplemented with 5% Glyceryl Oleate or with 2.5% Glyceryl Oleate plus 2.5% oleic acid. The absorption of tristearin, calcium, magnesium, and phosphorus was not altered. c42

>

The presence of Glyceryl Oleate within the intestinal lumen enhanced the intestinal absorption of macromolecules. Glyceryl Oleate-bile salt mixed micellar solutions were necessary adjuvants to potentiate heparin absorption. c43

-44

>

The use of Glyceryl Oleate as a micelle promoter in chickens alleviated the toxic effects of T-2 toxin, a secondary metabolite of several species of the genus Fusarium. c45

> Mixed micellar solutions containing taurocholate and Glyceryl Oleate prevented deoxycholate-induced malabsorption in the rat jejunum. c46

>

Micellar fat containing Glyceryl Oleate decreased the contractility of canine gastric muscles after stimulation with acetylcholine or 5-hydroxytryptophan. c47

>

A volume of 10 ml of micellar fat consisting of 0.25 mM Glyceryl Oleate, 0.5 mM oleic acid, and dog bile diluted by a salt solution was instilled into the duodena of dogs following intravenous injections of the following gastric stimuli: food, acetylcholine, or 5-hydroxytryptophan. Bile alone and saline did not produce these responses.



Glyceryl Oleate was a minor component (1.3%-6.7%) in Fruend water-in-oil adjuvant mixtures that were used to sensitize mice to a protein antigen. Although the protein in emulsions containing Glyceryl Oleate succeeded in producing Arthus reactions and delayed hypersensitivies, no conclusion could be reached on the potential adjuvant properties of Glyceryl Oleate as an individual ingredient. <48

)

Inhibition of cow's milk lipoprotein lipase by a human plasma apolipoprotein was reversed by the addition of Glyceryl Oleate to the reaction mixture. <49

)

The addition of Glyceryl Oleate (1 w/v %) to a culture of the fungus, Candida paralipolytica, increased the lipase activity. <50

) The free fatty acids tested did not significantly increase lipase activity over controls.

Glyceryl Oleate prevented the fusion of chicken myoblasts in vitro at concentrations ranging from 40 to 70 J.tg/ml under conditions that have been reported for erythrocytic fusion. <51

) Concentrations above 80 J.tg/ml were toxic to the myoblastic cultures.

The interaction of fusogenic lipids, such as Glyceryl Oleate, with erythrocyte ghosts was studied using fluorescence probes. <52

) Changes in the quantum yield, fluorescence intensity, and emission wavelength of the probe in the presence of Glyceryl Oleate were due to the production of a less ordered, functionally fluid membrane structure. The chemically related nonfusogenic lipid, glyceryl monostearate, had no effect on the observed fluorescence parameters.

The ability of Glyceryl Oleate to inhibit the antimicrobial activity of two imidazole antimycotic drugs against Candida was evaluated using an agar diffusion procedure. <531 Glyceryl Oleate decreased the diameter of the inhibition zone at a concentration of 0.25 mM. No decrease was observed at the lower concentrations of 0.13 mM and 0.06 mM.

The antimicrobial activity of Glyceryl Oleate and other polyhydric alcohols was assessed. <

54) Glyceryl Oleate had slight activity, causing inhibition of growth

of Corynebacterium sp. at concentrations above 1.40 J.tmol/ml. Other microorganisms, such as Streptococcus pyogenes, Nocardia asteroides, and Staphylococcus aureus, were not inhibited up to the highest concentration tested, 2.81 J.tmol/ml.

Glyceryl Oleate induced aggregation of nematodes (Bursaphelenchus lignicolus) as compared with untreated controls. <55

)

ANIMAL TOXICOLOGY

Acute Oral Toxicity

A sunscreen formulation containing Glyceryl Oleate (at 5%) was evaluated for acute toxicity upon oral administration to 10 Fischer rats. <

56l After a 14-day

observation period for signs of toxicity, the study directors concluded that the single 13 ml/kg dose was not lethal in rats.

Skin Irritation

Five studies using the single insult occlusive patch test were performed to evaluate the primary dermal irritation potential of Glyceryl Oleate at two concentrations. <57

-61

) A volume of 0.5 ml was placed on the clipped dorsal skin of



nine rabbits. Sites were graded for erythema and edema 2 and 24 h after exposure (maximum score for either erythema or edema = 4). In the three studies with undiluted Glyceryl Oleate, it was concluded that it had minimal skin irritation potential; erythema scores ranged from 0.5 to 1. <57

-59

) Similar results and conclusions were reported in the two studies using 50% Glyceryl Oleate in corn oil< 60

-61

) (Table 3). The dermal toxicity of a sunscreen formulation containing 5% Glyceryl Ole

ate was evaluated using three New Zealand White (NZW) rabbits. <56) Volumes of

0.5 ml were applied to the animals' clipped dorsal skin once daily for 4 days. After a 7-day assessment period for derrnal irritation, which was characterized by well-defined to moderate erythema, slight edema, and subsequent slight desquamation, the resultant irritation index was 3.0 (max = 8.0) (Table 3).

Ocular Irritation

Glyceryl Oleate was evaluated for ocular irritation in six rabbits using the Draize Eye Test. Undiluted and 50.0% in corn oil preparations were administered at a volume of 0.1 mi. The Draize system, <62

) which has a calculated maxi-

TABLE 3. Primary Skin Irritation and Dermal Toxicity of Glyceryl Oleate

Material tested

Glyceryl Oleate undiluted



Glyceryl Oleate 50% in corn oil


Glyceryl Oleate 5% in sunscreen formulation

Glyceryl Oleate at unspecified concentration in cosmetic formulation

•SIPT, single insult patch test.

No. of rabbits

9

9

9

9

9

3

10

Method

SIPP-occlusive

SIPT -occlusive

SIPT- ocClusive

SIPT -occlusive

SIPT -occlusive

Dermal toxicity of 0.5 ml applied to clipped dorsal skin once daily for 4 days

Subchronic dermal toxicity (28 days). 25.0% w/v formulation in corn oil applied to shaved abraded and intact skin 5 days per week for 4 weeks

bPII, primary irritation index. Maximum possible score = 8.00.

Conclusion Reference

Minimal skin irritation 57 Pllb = 0.72

Minimal skin irritation 58 Pll = 0.67



Practically nonexistent 61 skin irritation Pll = 0.33

Mild dermal irritation Pll = 3.0

Severe irritation at application site of treated rabbits; gross and microscopicalterations noted

56

66



mum irritation score of 110, was used to score the extent of irritation. In the two studies using undiluted Glyceryl Oleate, results were similar after 2 days of observation; mean scores were 0 and 1 in 110. Glyceryl Oleate produced minimal eye irritation. <63

·64

> The 50.0% Glyceryl Oleate preparation was also minimally irritating, and the mean scores were 1 and 2 for Days 1 and 2, respectively< 65

>

(Table 4). A fragrance preparation containing Glyceryl Oleate at 19.0% concentration

was tested in rabbits with the standard Draize Test. The total mean score of 12 on Day 1 decreased to 8 on Day 2, 6 on Day 4, and 2 on Day 7. Individual mean scores for two of the six rabbits tested were in the 25 to 35 range on the first day, decreasing to approximately 18 by Day 4 and to 7 by Day 7. All other rabbits had negative to transient minimal responses. The formulation produced moderate eye irritation <67 > (Table 4).

A 0.1 ml volume of a sunscreen formulation containing 5% Glyceryl Oleate was evaluated for eye irritation in six NZW rabbits. <56

> Scoring was performed 1 h after treatment and on Days 1, 2, 3, and 7. Slight conjunctivitis was observed after 1 h, clearing within 24 h, and no signs of irritation to other tissues were noted (Table 4).

Subchronic Dermal Toxicity and Phototoxicity

A 28-day subchronic dermal toxicity study assessed the safety of a cosmetic formulation containing Glyceryl Oleate (at an unspecified concentration) in 10 albino rabbits. <66

> A 25.0% (w/v) solution of the formulation in corn oil was ap" plied to shaved skin that had been either abraded or left intact. The 2.0 ml/kg

TABLE 4. Ocular Irritation of Glyceryl Oleate

Material tested




Glyceryl Oleate 19.0% in fragrance preparation

Glyceryl Oleate 5% in sunscreen formulation

No. of rabbits

6

6

6

6

6

•All studies followed methods of Draize. ' 61'

Results

Minimal eye irritation; mean score - 1 (max score - 11 0) on Day 1 following treatment

Minimal eye irritation; mean score - 1 on Day 1

Minimal eye irritation; mean score - 1 on Day 1

Moderate eye irritation; mean score - 12 on Day 1, 8 on Days 2 and 3, 6 on Day 4, 2 on Day 7

Slight conjunctivitis 1 h after treatment; cleared within 24 h

Reference•

63

64

65

67

56



dose was left in contact with the skin for an indefinite period of time. The rabbits were treated 5 days per week for a period of 4 weeks. The major response to repeated administration of this formulation was "severe irritation" of the skin at the site of application. Alterations included erythema, severe edema, and desquamation, fissures, hemorrhages, and pustules. Microscopic changes included acanthosis, hyperkeratosis, focal epidermal ulceration, focal dermal inflammation, abscess formation, and/or focal escharosis at some of the treated sites. No skin reactions were noted in controls. Other results (e.g., mortality, gross behavior/appearance, and results of hematological, clinical chemistry, and urine analyses) were negative or not treatment-related (Table 3).

Three formulations containing two sunscreen ingredients (maximum concentrations 2.0% and 4.0%) were evaluated in a 28-day subchronic dermal toxicity/phototoxicity study in NZW rabbits. <68

> The sunscreens contained Glyceryl Oleate at a 5% concentration. Topical applications of 6 mg cream per cm 2 to clipped dorsal intact and abraded skin sites of the animals (four animals per group) were followed by a 4-minute exposure (at one-half the minimum erythemal dose) to UV radiation (Westinghouse FS-20 sunlamp) and a 6-h occlusion of the test sites. This treatment was repeated 5 days each week followed by 2 nontreatment days for 4 weeks. Animals were then observed for 2 weeks before necropsy. The four deaths (one control, three treated) were reportedly due to naturally occurring chronic enteritis. Body weights, mean group feed consumption, and hematological and urinalysis data from treated animals reflected normal variability. The organ:body weight disparity of some treated animals with controls was not considered toxicologically significant. All three formulations caused slight dermal irritation during the first week of treatment that was similar to that observed in several control animals exposed to UV light alone. Maximal irritation during the second week, which was sustained through the remainder of the treatment period, was characterized by slight to moderate erythema, slight edema, and scaly desquamation. The severity of dermal irritation was equivalent at both abraded and intact sites. Normal healing occurred during the 2-week observation period following treatment.

Subchronic and Chronic Toxicity of Glycerol and Oleic Acid

Toxicological data on glycerol and oleic acid, metabolic products of Glyceryl Oleate, were obtained from subchronic and chronic ingestion studies used to regulate these GRAS substances. <30

·69

-73 >

Subchronic Oral Toxicity of Glycerol

Rats fed glycerol at concentrations up to 20% in their diets or by stomach tube for periods of 4-11 weeks had no adverse effects that could be attributed to glycerol consumption. <74

-79) Criteria, such as body weight gain, food and water intake, resistance to cold, mortality, behavior, blood chemistry, hematology, and gross and microscopic features of major internal organs and tissues, were observed.

Oral doses of up to 3 g of undiluted glycerol given three times per day for a total of eight doses resulted in hyperemia, petechial hemorrhages, and erosion of the gastrointestinal mucosa of rats and dogs. <80

>


ASSESSMENT: Gl YCERYL OLEATE 401

Volumes greater than 5 ml of a 50% aqueous saline solution of glycerol administered to guinea pigs by stomach tube or from a drinking cup daily for a period of 30-40 days produced signs of acute toxicity and death. <81

> Doses of 10 ml of the 50% solution for 30-40 days were well tolerated by rabbits. <81

> The red blood cell count of the treated guinea pigs had decreased. No gross pathological changes and no glycerol-related changes in plasma or erythrocytic cholesterol concentrations were found in either species.

Three-month administration of up to 20% solutions of glycerol to rats as drinking water resulted in the death of 2/12 rats receiving the highest concentration and temporary impairment in the development of the remaining rats. <77

>

Growth of rats was normal at concentrations of glycerol of less than or equal to 10%. Temporary growth impairment was observed in rats administered 20% glycerol solutions for 3 months. <82 >

After the oral administration of 2.0 ml/kg doses of glycerol to two dogs twice weekly for 4 months, growth was normal and no abnormalities were found in urine and the internal organs. <83

>

The feeding of glycerol to rats at concentrations up to 41% (as a dietary supplement) for 21-25 weeks did not produce changes in growth or in the liver, kidneys, or intestines of these animals. <74

> In another study, subnormal growth was found in rats fed diets containing greater than 30% glycerol for 20 weeks. <

84>

Pathological changes were observed in rats fed diets containing glycerol at concentrations greater than 10%. The most marked changes were hydropic and fatty changes of hepatocytes.

Subchronic Dermal Toxicity of Glycerol

Doses of 0.5-4.0 ml (0.6-5 g) per kg natural or synthetic glycerol were applied to the shaved dorsal skin of 24 albino rabbits for an 8-h exposure, 5 days per week, for 18 weeks. <85

> No evidence of skin irritation was observed; no abnormalities were found in urine or blood or after gross and microscopic examinations of internal organs.

Chronic Oral Toxicity of Glycerol

The only untoward effect in a 6-month study of rats given 5% solutions of either synthetic or natural glycerol as drinking water was calcified masses in the renal tubules of 6/10 rats. <86

> Administration of 1.0 ml/kg of a 50% aqueous glycerol solution to 60 rats for 6 months had no adverse effects on development, survival, internal organs, skeletal system, or hepatic glycogen. <77

>

Three dogs fed glycerol at a concentration of 35% (as a dietary supplement) for 31 weeks had normal growth.< 74

> In the 14-week period following a reduction in feed consumption, treated dogs lost an average of 16% of their previously attained weight; control dogs maintained their weight. Diuresis was observed in treated dogs, but no hemoglobinuria, albuminuria, liver degeneration, or gross or microscopic abnormalities of internal organs were found.

Growth impairment, reduced activity, and dull coats were observed in rats fed 61% glycerol substituted for starch for 40 weeks. These changes were considered due to a lack of starch rather than to glycerol toxicity. Rats fed 20% and 40% glycerol diets for 40 weeks had normal growth. <74

>



In 2-year toxicity studies using rats and dogs fed 0, 5, 10, and 20% glycerol, no treatment-related adverse effects were found. c85

'871 Although Hine et al. c851

observed high incidences of albuminuria and glycosuria in treated rats and high liver:body weight ratios in females fed diets with 20% glycerol, they concluded that glycerol at concentrations below 20% would not cause untoward effects in rats.

Subchronic Oral Toxicity of Oleic Acid A volume of 10 ml of oleic acid (approximate dose 2 g/kg) administered to

four albino rabbits by stomach tube every other day for 4 days resulted in the death of one of the four rabbits. c881 Other signs included hair loss and seborrheic lesions on the rabbits' ears. No adverse effects were observed after administration of a volume of 2.5 ml (approximate dose 0.6 g/kg).

Feeding of a 5% oleic acid diet (approximate dose 6 g/kg daily) to chicks for 4 weeks had no adverse effect. c891

Chronic Toxicity of Oleic Acid The growth rates of albino mice receiving weekly subcutaneous injections of

0.25 ml and 0.5 ml of a 5% oleic acid emulsion (approximate dose 12-15 g/kg) for 15 months were normal. c9o>

Rats fed a 15% Oleic Acid diet for 5 months had normal development and good general healthY1

> A progressive reduction in spermatogenesis and prolonged estrus cycles (although most females bore living young) were noted; these signs were considered typical of animals fed diets deficient in essential fatty acids.

Carcinogenicity

Several egg lipids were examined for their potential to produce brain tumors in mice of the T.M. strain. en> Purina mice chow, which was fed to controls ad libitum, corn oil, cholesterol, Glyceryl Oleate, corn oil plus cholesterol, or Glyceryl Oleate plus cholesterol were mixed with sugar and presented to mice once a day. Doses of these supplements were 50-100 mg/mouse per day Glyceryl Oleate, 4-5 mg/mouse per day cholesterol, and 100-150 mg/mouse per day corn oil; the purity of these supplements was not stated. Four-week-old mice were fed these diets and then bred within the same group. Their offspring were maintained on the same diets as their parents from birth "until they died or became moribund and were killed." Survival rates for the individual groups were not provided. The incidence of brain tumors in treated mice is shown in Table 5. The report contained general histopathological descriptions of the tumors; however, no specific tumor type induced by Glyceryl Oleate was described. The diets supplemented with lecithin, cholesterol, and cholesterol, in combination with any other lipid, induced brain tumors in the largest number of mice.

In a similar experiment, the carcinogenicity of Glyceryl Oleate was evaluated in T.M. strain mice that were fed Purina Chow supplemented with refined corn oil (Group 2), crude corn oil (Group 3), refined corn oil plus up to 1.5% free fatty acids, oleic and linoleic acids (Group 4), and Glyceryl Oleate (Group 5) at concentrations of 200 mg/mouse per day. c931 Controls (Group 1) were fed


ASSESSMENT: Gl YCERYL OLEATE 403

TABLE 5. Incidence of Brain Tumors in Mice Fed Various Egg Lipids( 921

Total no. of No. of No. of mice Diet supplement mice treated mice examined a with brain tumors

Control, no supplement 360 188 0

Corn oil 159 11

Cholesterol 212 80 20

Glyceryl Oleate 144 63 3

Corn oil and cholesterol 106 22 7

Glyceryl Oleate and cholesterol 158 64 7

aJt was not stated whether or not the mice that were not examined within each group died, and, if they died, whether or not their deaths were associated with their respective dietary supplements.

Purina Chow alone. Offspring of the intragroup bred mice were maintained on the same diets for a total of four-seven generations of mice. Mice were killed when they were observed to lose weight rapidly. Three of the 195 control mice in Group 1 developed gastric papillomas and squamous cell carcinomas, and none developed pyloric or intestinal tumors. Gastric papillomas were also found in 6/209 mice of Group 2, 49/196 mice of Group 3, 87/328 mice of Group 4, and 31/166 mice of Group 5 (Giyceryl Oleate-supplemented diet). Fewer squamous cell carcinomas were observed in all treatment groups: Group 2, 1 /209; Group 3, 6/196; Group 4, 1 0/328; Group 5, 6/166. Pyloric tumors were also recorded for all treatment groups at the following frequencies: Group 2, 2/209; Group 3, 9/196; Group 4, 41 /328; Group 5, 31/166. Free fatty acids in the preparations fed to the mice that developed gastric tumors were considered the cause of the tumors; however, the relative purity of the Glyceryl Oleate was not detailed. Detailed gross and microscopic descriptions of the tumors were recorded.

Antitu morigen icity

The in vivo antitumor activity of Glyceryl Oleate was studied using implanted Ehrlich ascites tumors in mice. <94

> Saline solutions at two doses (6.0 and 1.5 mg/mouse per day) of Glyceryl Oleate were administered once daily for 5 successive days to two mice per dose. Tumor growth and body weight gain after 7 days and life spans were recorded. Whereas control mice died within 17 days, both doses of Glyceryl Oleate prolonged the survival period of the mice ( > 30 days at 6.0 mg and an average of 24 days at 1.5 mg). Although both doses resulted in an increase in body weight over 7 days, inhibition of tumor growth was observed in mice only at the higher dose. Moderate tumor growth occurred at the lower dose.

CLINICAL ASSESSMENT OF SAFETY

Dermal Irritation

Glyceryl Oleate, used in hand cream at 1.5%, was evaluated for primary dermal irritation in 15 and 30% aqueous preparations. <95 > Twenty subjects participated in the single insult occlusive patch test using the Draize-Shelanski tech-



nique. The 15% concentration yielded 18 negative responses; the remaining 2 subjects had scores of 0.5 and 1 (max = 3). Seventeen individuals had negative responses, and 3 had scores of 1 after treatment with the 30% solution (Table 6).

A single insult occlusive patch test was performed using 20 panelists by applying a fragrance preparation that contained 19.0% Glyceryl Oleate. <96

> Negative results were found in 17 of 20 subjects (doubtful reactions were observed in 3 of 20 subjects), and the formulation's skin irritation potential was "practically nonexistent'' (Table 6).

Cumulative Dermal Irritation

The Lanman-Maibach test< 97·98

> was used to assess the cumulative irritation potential of two sunscreen formulations containing 5% Glyceryl Oleate. <99

> A dose of 50 {ti/cm 2 was administered to the backs of 10 subjects under 23-h closed patches for a total of 21 consecutive applications. Sites were cleaned before scoring and at reapplication at the 24th hour. The total converted numerical scores for all applications and subjects of the two formulations were 23 and 38 (maximum score = 630), ranking them as mild materials causing no experimental irritation. Positive responses to both formulations were not observed until at least the 12th application in most subjects. Most of the points for the cumulative. total scores were contributed by 1 subject alone (22/23 points, 26/38 points), whereas the remaining 9 subjects had individual scores of 0-3 (Table 6).

Sensitization

A repeated insult patch test (RIPT) using 200 people was used to evaluate a 15% aqueous solution of Glyceryl Oleate as a primary irritant, fatiguing agent, and/or sensitizer. <100

> Sixteen 24-h occlusive patches were applied to the upper arm on Mondays, Wednesdays, and Fridays. Nontreatment periods were stated to be the days between alternate day applications and on weekends. No signs of skin irritation were observed after exposure to Glyceryl Oleate in any of the applications (Table 6).

An RIPT with a sunscreen formulation containing 5% Glyceryl Oleate was conducted using an occlusive patch technique. <101

> Ten 24-h induction patches on Tuesdays, Thursdays, and Saturdays (sites were evaluated after removal of each patch) were followed by a 12-16-day nontreatment period and a 24-h challenge patch at an adjacent site. These challenge sites were then evaluated immediately after patch removal and 24 h later. None of the 15 subjects participating in this study alone had positive reactions during the induction phase or when challenged. Of the 37 others who were being tested simultaneously for photoallergic and phototoxic responses to treatment, 2 subjects had transient reactions of slight erythema (scores of 1 on scale of 0-4) to induction patches, and all subjects had no reaction to the challenge patch (Table 6).

Photoallergy and Phototoxicity

The potential of a sunscreen formulation containing 5% Glyceryl Oleate for inducing photoallergy and phototoxicity in humans was evaluated by modifications of an RIPT. <101

> Approximately 200 mg of the formulation was applied under an occlusive patch to the inner forearms of 29 subjects for the photoal-



lergy test and of 10 subjects for the phototoxicity test. After a 24-h exposure period, the contact sites were evaluated after patch removal and irradiated with UVA light (15 minutes at 4400 p.W/cm 2

). The sites of subjects in the phototoxicity test were then evaluated immediately following irradiation and 24 h and 48 ·h later. The 24-h patch application and irradiation were repeated 10 times for subjects in the photoallergy test on Mondays, Wednesdays, and Thursdays. After a 12-16 day nontreatment period, 24-h challenge patches were applied to adjacent sites. Photoallergy test sites were evaluated before and after irradiation upon patch removal in both induction and challenge phases. Scoring was performed at 48 and 72 h after application of challenge patches. No skin reactions were observed in the 10 subjects participating in the phototoxicity test, and only 1 photoallergy test subject (n = 29) had a grade 1 reaction (scale 0-4) to the sixth induction patch at the nonirradiated control site. No positive reactions to induction or challenge patches were observed at any irradiated site (Table 6).

Oral Exposure to Glycerol

Data from subchronic human studies on the oral administration of glycerol, a metabolic product of Glyceryl Oleate, were used in the safety assessment process of glycerol for the federal regulation of GRAS substances. (30

·69

>

SUMMARY

Glyceryl Oleate, the glyceryl 1-monoester of oleic acid, is dispersible in water and soluble in acetone, simple alcohols, and cottonseed oil. Glyceryl Oleate is manufactured by the partial hydrolysis of corresponding tri- and diglycerides, by esterification of glycerol with oleic acid, or by glycerolysis of common fats and oils.

Glyceryl Oleate is used primarily in cosmetic products as an emulsifier and was listed as an ingredient in 716 of the cosmetic formulations reported to the FDA in 1981. The FDA table had Glyceryl Oleate concentrations ranging from :50.1 to 5% in formulations that were predominantly lipsticks, eye shadows, makeup bases, and skin care preparations.

Monoglycerides of edible fats or oils are considered GRAS and indirect food additives for human consumption by the FDA. Glyceryl Oleate can be used as a prior-sanctioned food ingredient and as a direct and indirect food additive. The pharmaceutical industry uses Glyceryl Oleate as an inert carrier compound and to enhance intestinal drug absorption.

Oral administration of a single 13 ml/kg dose of a sunscreen formulation containing 5% Glyceryl Oleate to rats produced no signs of toxicity and no lethality.

Undiluted and 50% in corn oil concentrations of Glyceryl Oleate used in dermal irritation studies with rabbits were found to be minimally irritating. A volume of 0.5 ml of a sunscreen formulation containing 5% Glyceryl Oleate produced erythema and slight edema in rabbits.

Minimal to moderate eye irritation was produced by undiluted Glyceryl Oleate, 50% Glyceryl Oleate in corn oil, and a fragrance preparation containing


TABLE 6. Clinical Assessment of Safety of Glyceryl Oleate

Material tested

Glyceryl Oleate

Glyceryl Oleate

G1yceryl Oleate

Fragrance preparation

Sunscreen formulation

Glyceryl Oleate

concentration

15% aqueous

30% aqueous

15% aqueous

19.0%

5%

Type of test

Test for skin irritation by Draize-Shelanski SIOPP

Test for skin irritation by Draize-Shelanski SIOPT

RIPTb (16 patches, Mon., Wed., Fri.)

Test for skin irritation by SIOPT

21-day Cumulative Irritancy Test

No. of humans

20

20

200

20

10

Results/Comments

18/20 had score of 0 1/20 had score of 1/2 1/20 had score of 1 (max - 3)

17/20 had score of 0 3/20 had score of 1 {max - 3)

No signs of skin irritation observed during induction or challenge (weekends considered nontreatment period)

17/20 had score of 0 3/20 had score of ± (max- 4)

Total converted numerical score of 23 (max - 630); mild material causing no irritation

Reference

95

95

100

96

99


Sunscreen formulation 5% 21-day Cumulative Irritancy 10 Total converted numerical score of 38 99 :> Test (max = 630); mild material causing "' "' m

no irritation Ill Ill

Sunscreen formulation 5% RIPT 52 15/52 were involved in RIPT alone; 101 ~ m

none of the 15 had positive reactions; z 37/52 were involved in simultaneous ::1 photoallergy and phototoxicity test- C'l

r-ing; 2/37 had transient, slight ery- -(

n thema to induction patches; no reac- m

lions to challenge patches observed ~ I""

Sunscreen formulation 5% Photoallergy test by RIPT + 29 One subject had a score of 1 to the 101 0 UVA irradiation sixth induction patch at a nonirradi-

I"" m

ated control site (max - 4); no posi- :> -4

tive reactions to induction or chal-m

lenge patches at any irradiated site

Sunscreen formulation 5% Phototoxicity test single 10 No skin reactions observed 101 patch test + UVA irradia-tion

•SIOPT, single insult occlusive patch test. bRIPT, repeated insult patch test.



19.0% Glyceryl Oleate when administered to rabbits. A formulation containing 5% Glyceryl Oleate administered at a 0.1 ml dose to rabbit eyes induced slight conjunctivitis.

Daily applications of 2.0 ml/kg of a 25.0% corn oil solution of a formulation containing Glyceryl Oleate for 20 days produced severe dermal irritation in rabbits. In another 4-week dermal toxicity/phototoxicity study, product formulations containing varying concentrations of two sunscreen ingredients produced slight, reversible dermal irritation. Each sunscreen ingredient contained 5% Glyceryl Oleate.

Glyceryl Oleate administration was associated with development of a few brain tumors (3 tumors in 63 mice) in a two-generation study in mice of the T.M. strain whose feed was supplemented with 50-100 mg/mouse per day Glyceryl Oleate. Digestive tract tumors were found in T.M. strain mice fed 200 mg/mouse per day Glyceryl Oleate (feed supplement) for four-seven generations and were considered due to free fatty acid impurities. The Expert Panel found the results of these studies equivocal.

Doses of 1.5 and 6.0 mg/mouse per day of Glyceryl Oleate in saline increased the survival period of mice with implanted Ehrlich ascites tumors; the higher dose inhibited tumor growth.

Two aqueous Glyceryl Oleate preparations (15% and 30% concentrations) and a fragrance preparation containing 19.0% Glyceryl Oleate were negative for cutaneous irritation when tested on human skin using single insult occlusive patch tests.

Two sunscreen formulations containing 5% Glyceryl Oleate were considered mild compounds and caused no irritation in a cumulative occlusive patch test using human subjects.

No signs of irritation or sensitization were observed in humans after repeated insult patch testing of a 15% aqueous Glyceryl Oleate preparation and a sunscreen formulation containing 5% Glyceryl Oleate. A few subjects involved in simultaneous photoallergy and phototoxicity tests had slight, transient erythematous responses. No positive reactions were observed at any irradiated site during induction and challenge phases of the photoallergy test.

The metabolic products of Glyceryl Oleate are glycerol and oleic acid. The use of these compounds in and for foods is regulated by the FDA. Subchronic and chronic toxicity data from studies with animals and humans that were used in the safety assessment of glycerides, glycerol, oleic acid and sodium oleate are presented in this report.

CONCLUSION

Based on the data from animal and human studies included in this report, the CIR Expert Panel concludes that Glyceryl Oleate is safe as a cosmetic ingredient in the present practices of use and concentration.



ACKNOWLEDGMENT

Mauri Y. Okamoto, Scientific Analyst and writer, prepared the technical analysis used by the Expert Panel in developing this report. Word processing for this report was performed by Karen Swanson.

REFERENCES

1. ESTRIN, N.F., CROSLEY, P.A., and HAYNES, C.R. (eds.}. (1982). Cosmetic, Toiletry and Fragrance Association (CTFA) Cosmetic Ingredient Dictionary, 3rd ed. Washington, D.C.: Cosmetic, Toiletry and Fragrance Association.

2. ESTRIN, N.F., HAYNES, C.R., and WHELAN, ].M. (eds.}. (1982}. CTFA Compendium of Cosmetic Ingredient Compositions. Cosmetic Ingredient Descriptions. Washington, D.C.: Cosmetic, Toiletry and Fragrance Association.

3. MALOVA, I.D., GRETSKII, V.M., BALANDINA, E.A., KABACHNYI, G.l., and LEKHTER, A.E. (1980}. Study of the emulsifying properties of esters of glycerin and higher fatty acids. Farmatsiya (Moscow) 29(4), 19-22.

4. SENZEL, A.]. (ed.). (1977}. Newburger's Manual of Cosmetic Analysis, 2nd ed. Washington, D.C.: AOAC. 5. KRESZE, G., BEDERKE, K., and SCHAEVFFELHUT, F. (1965}. Analysis of mixtures of mono- and diglycer

ides by gas chromatography and nuclear magnetic resonance. Z. Anal. Chem. 209(2}, 329-337. 6. HORWITZ, W. (ed.). (1980). Official Methods of Analysis of the Association of Official Analytical Chemists

(AOAC), 13th ed. Washington, D.C.: AOAC. 7. SWERN, D. (ed.}. (1979). Bailey's Industrial Oil and fat Products, 4th ed. New York: john Wiley and Sons,

Vol. 1. 8. WINDLHOLZ, M., BUDAVARI, S., BLUMETII, R.F., and OTIERBEIN, E.S. (eds.}. (1983). The Merck

Index, 1Oth ed. Rahway, N.J.: Merck and Co., Inc. 9. GREENBERG, L.A., and LESTER, D. (1954). Handbook of Cosmetic Materials. New York: lnterscience

Publishers. 10. WEAST, R.C. (ed.}. (1982). Handbook of Chemistry and Physics, 63rd ed. Boca Raton, FL.: CRC Press. 11. FOOD AND DRUG ADMINISTRATION (FDA). (1981). Computer printout of voluntary submission of

cosmetic ingredient data. 12. CODE OF FEDERAL REGULATIONS (CFR). (1984). Title 21, Food and Drugs, Sections 172.515, 175.105,

175.300, 175.320, 176.210, 181.27, 182.90, 182.4505. Washington, D.C.: U.S. Government Printing Office.

13. FOOD CHEMICAL NEWS (FCN). (February 14, 1983). FDA Proposes GRAS affirmations for glycerides. 24(49}, 40.

14. PROCTER AND GAMBLE CO. (September 8, 1950). Submission of unpublished data to FDA. The comparative nutritive value of certain mono-, di-, and tri-glycerides. FAP 9A0018 Vol. 1, pp. 2-108.

15. HARRIS, R.S., and SHERMAN, H. (1954). Comparison of the nutritive values of mono-, di- and triglycerides by a modified pair-feeding technique. Food Res. 19(2), 257-262.

16. MATISON, F.H., ALEXANDER, ].C., BAUR, F.]., and RELLER, H.H. (1956). Short-term feeding studies on acetin fats.]. Nutr. 59, 277-285.

17. AMES, R., O'GRADY, M.P., EMBREE, N.D., and HARRIS, P.L. (1951). Molecularly distilled monoglycerides. Ill. Nutritional studies on monoglycerides derived from cottonseed oil.]. Am. Oil Chem. Soc. 28, 31-33.

18. BRAUN, W.Q., and SHREWSBURY, C.L. (1941). The nutritive properties of monoglycerides. Oil and soap. 18(12), 249-250.

19. ROSNER-HIXSON LABORATORIES. Uune 29, 1959). Submission of unpublished data to FDA. Digestibility of monoglyceride citrate by in vitro and in vivo methods. GRM 23 vol. 5, pp. 1081-1085.

20. ORTEN, j.M., and DAJANI, R.N. (1957). A study of the effects of certain food emulsifiers in hamsters. Food Res. 22, 529-541.

21. TIDWELL, H.C. (1957). Absorption of monoglycerides. Am. j. Physiol. 189(3), 537-540. 22. FCN. Uanuary 28, 1985). FDA GRAS affirmation proposals pending on December 31, 1984. 26(47),

11-12.



23. THOMPSON, E.D., CARTER, S.B., and MANRING, G.L. (1978). Antimicrobial agent for topical use. Ger. Offen. Patent No. 2748399.

24. MURANUSHI, N., NAKAJIMA, Y., KINUGAWA, M., MURANISHI, S., and SEZAKI, H. (1980). Mechanism for the inducement of the intestinal absorption of poorly absorbed drugs by mixed micelles. II. Effect of the incorporation of various lipids on the permeability of liposomal membranes. Int. j. Pharm. 4{4), 281-290.

25. ASHER, W.j., BOVEE, K.C., VOGLER, T.C., HAMILTON, R.W., and HOLTZAPPLE, P.G. (1980). Secretion moderated release of urease from liquid membrane capsules. Trans. Am. Soc. Artif. Intern. Organs 26, 120-3.

26. ECKERT, T., and KEMPER, F.H. (1980). Enterally highly absorbable pharmaceutical preparations. Austrian Patent No. 360161.

27. GRAHAM, N.B., RASHID, A., and RAO, K.P. (1983). Unsaturated monomer reaction products with glycerin or monoglycerides for encapsulation of active materials. Eur. Pat. Appl. Patent No. 76158.

28. LAPRADE, R., GRENIER, F., LAPOINTE, j.Y., and ASSELIN, S. (1982). Effects of variation of ion and methylation of carrier on the rate constants of macrotetralide-mediated ion transport in lipid bilayers. j. Membr. Bioi. 68{3), 191-206.

29. CRAMP, F.C., and LUCY, j.A. (1974). Glyceryl monooleate as a fusogen for the formation of heterokaryons and interspecific hybrid cells. Exp. Cell Res. 87, 107-110.

30. FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY (FASEB), Life Sciences Research Office. (1975). Evaluation of the health aspects of glycerin and glycerides as food ingredients. U.S. Department of Commerce. NTIS PB-254536.

31. TWU, j-S, GARFINKEL, A.S., and SCHOTZ, M.C. (March 7, 1984). Hepatic lipase. Purification and characterization. Biochim. Biophys. Acta 792(3), 330-337.

32. BICKERSTAFFE, R., and ANNISON, E.F. (1969). Triglyceride synthesis by the small intestinal epithelium of the pig, sheep, and chicken. Biochem. j. 111(4), 419-429.

33. BORGSTROM, B. (1974). Fat digestion and absorption. Biomembranes 48(0), 555-620. 34. BRINDLEY, D.N. (1974). The intracellular phase of fat absorption. Biomembranes. 48(0), 621-671. 35. FLORKIN, M., and STOTZ, E.H. (eds.). (1971). Lipid Metabolism. Comprehensive Biochemistry. New

York: Elsevier Publ. Co., Vol. 18. 36. SMITH, L.C., and SCOW, R.O. (1979). Chylomicrons. Mechanism of transfer of lipolytic products to cells.

Prog. Biochem. Pharmacal. 15, 109-138. 37. ELDER, R.L. (ed.). (1982). Final report on the safety assessment of decyl and isodecyl oleates. J. Am. Coli.

Toxicol. 1(2), 85-95. 38. STUMPF, P.K. (1969). Metabolism of fatty acids. Ann. Rev. Biochem. 38, 159-212. 39. FULCO, A.j. (1974). Metabolic alterations of fatty acids. Ann. Rev. Biochem. 43, 215-241. 40. COSMETIC INGREDIENT REVIEW (CIR). (1985). Scientific literature review of Oleic Acid, Lauric Acid,

Palmitic Acid, Myristic Acid and Stearic Acid. 41. FELDMAN, S., and GIBALDI, M. (1969). Physiologic surface-active agents and drug absorption. VI. Bile

salt-induced permeability changes in the isolated rat intestine. Proc. Soc. Exp. Bioi. Med. 132(3), 1031-1033.

42. TADAYYON, B., and LUTWAK, L. (1969). Interrelation of triglycerides with calcium, magnesium, and phosphorus in the rat. j. Nutr. 97(2), 246-254.

43. TOKUNAGA, Y., MURANISHI, S., and SEZAKI, H. (1978). Enhanced intestinal permeability to macromolecules. I. Effect of monoolein-bile salts mixed micelles on the small intestinal absorption of heparin. j. Pharmacobio-Dyn. 1(1), 28-38.

44. TANIGUCHI, K., MURANISHI, S., and SEZAKI, H. (1980). Enhanced intestinal permeability to macromolecules. Part 2. Improvement of the large intestinal absorption of heparin by lipid surfactant mixed micelles in rat. Int. j. Pharm. 4, 219-228.

45. COFFIN, J.L., and COMBS, G.F. (1981 ). Impaired vitamin E status of chicks fed T-2 toxin. Poult. Sci. 60{2), 385-392.

46. LAMBADUSURIYA, S.P., GUIRALDES, E., and HARRIES, j.T. (1975). Influence of mixtures of taurocholate, fatty acids, and monoolein on the toxic effects of deoxycholate in rat jejunum in vivo. Gastroenterology 69(2), 463-469.

47. ANDERSON, J.J.. BOLT, R.J .• ULLMAN, B.M., and BASS, P. (1968). Effect of bile and fat on gastric motility under the influence of various stimulants. Am. j. Dig. Dis. 13(2), 157-167.

48. CROWLE, A.j., and HU, C.C. (1966). A comparison of n-hexadecane and mineral oil emulsions in induction of hypersensitivity in mice. Proc. Soc. Exp. Bioi. Med. 123(1), 94-97.



49. BAGINSKY, M.L., and BROWN, W.V. (1976). Effects of monoolein on hydrolysis of triglyceride by lipoprotein lipase in the presence of an inhibitory apolipoprotein. Physiol. Chern. Phys. 8(3), 197-206.

50. OTA, Y., SUZUKI, M., and YAMADA, K. (1968). Lipids and related substances inducing the lipase production by Candida paralipolytica. Agr. Bioi. Chern. 32(3), 390-391.

51. NAKORNCHAI, S., FALCONER, A.R., FISHER, D., GOODAll, A.H., HALLINAN, T., and LUCY, j.A. (1981). Effects of retinol, fatty acids and glycerin monooleate on the fusion of chick embryo myoblasts in vitro. Biochim. Biophys, Acta 643, 152-160.

52. KENNEDY, A., and RICE-EVANS, C. (1976). A spectrofluorimetric study of the interaction of glycerol monooleate with human erythrocyte ghosts. FEBS lett. 69(1), 45-50.

53. YAMAGUCHI, H. (1977). Antagonistic action of lipid components of membranes from Candida albicans and various other lipids on two imidazole antimycotics, clotrimazole and miconazole. Antimicrob. Agents Chemother. 12(1), 16-25.

54. CONLEY, A.j., and KABARA, ].]. (1973). Antimicrobial action of esters of polyhydric alcohols. Antimi· crob. Agents Chemother. 4(5), 501-506.

55. TOMINAGA, Y., NAGASE, A., KUWAHARA, Y., and SUGAWARA, R. (1982). Aggregation of Bursaphel· enchus lignicolus (Nematoda: Aphelenchoididae) to several compounds containing oleyl group. Appl. Entomol. Zool. 17(1), 46-51.

56. COSMETIC, TOILETRY AND FRAGRANCE ASSOCIATION (CTFA). Uuly 20, 1981). Submission of unpublished data by CTFA. Rat oral toxicity, rabbit dermal irritation and rabbit ocular irritation studies on a sun· screen formulation containing 5 percent Glyceryl Oleate. (2-47-6). •

57. CTFA. (February 27, 1978). Submission of unpublished data by CTFA. Rabbit primary dermal irritation study on undiluted Glyceryl Oleate. (2·47·9).*

58. CTFA. (August 28, 1978). Submission of unpublished data by CTFA. Rabbit primary dermal irritation study on undiluted Glyercyl Oleate. (2-47-10).*

59. CTFA. (May 7, 1979). Submission of unpublished data by CTFA. Rabbit primary dermal irritation study on undiluted Glyceryl Oleate. (2·47-11). •

60. CTFA. (November 15, 1976). Submission of unpublished data by CTFA. Rabbit primary dermal irritation study on 50.0 percent Glyceryl Oleate in corn oil. (2-47-7). •

61. CTFA. (April 25, 1977). Submission of unpublished data by CTFA. Rabbit primary dermal irritation study on 50.0 percent Glyceryl Oleate in corn oil. (2-47-8). •

62. DRAIZE, j.H. (1959). In: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. Austin, Texas: The Association of Food and Drug Officials of the United States.

63. CTFA. (April 25, 1977). Submission of unpublished data by CTFA. Rabbit ocular irritation study on undi· luted Glyceryl Oleate. (2-47-4). •

64. CTFA. (August 28, 1978). Submission of unpublished data by CTFA. Rabbit ocular irritation study on undiluted Glyceryl Oleate. (2-47-5). *

65. CTFA. (November 2, 1976). Submission of unpublished data by CTFA. Rabbit ocular irritation study on 50.0 percent Glyceryl Oleate in corn oil. (2·47-3). *

66. INDUSTRIAL BIO-TEST LABORATORIES. (August 30, 1973). Submission of unpublished data by CTFA. Subchronic dermal toxicity study in rabbits on a product containing Glyceryl Oleate at unspecified con· centration. (2-47-15). •

67. CTFA. (April 8, 1984). Submission of unpublished data by CTFA. Rabbit ocular irritation study on a fragrance preparation containing 19.0 percent Glyceryl Oleate. (2-47-1).*

68. CTFA. (October, 1977). Submission of unpublished data by CTFA. Subchronic dermal toxicity and phototoxicity study in rabbits on products containing sunscreen ingredients with 5 percent Glycery.l Oleate. (2-47-14). *

69. INFORMATICS. (1973). Monograph on glycerin and glycerides. DHEW Contract No. FDA 72-104. NTIS PB-221 227/2.

70. INFORMATICS. (1973). Monograph on vegetable oils, oleic acid, and linoleic acid. Vol. 1. DHEW Contract No. FDA 72-1 04. NTIS PB-228 546/8.

71. TRACOR JITCO. (1974). Monograph on sodium salts of fatty acids. DHEW Contract No. FDA 72-100. NTIS PB-241 968/7.

*Available upon request: Director, Cosmetic Ingredient Review, 1110 Vermont Ave., NW, Washington, DC 20005.



72. FASEB. (1977). Evaluation of the health aspects of coconut oil, peanut oil, and oleic acid as they may migrate to food from packaging materials, and linoleic acid as a food ingredient. DHEW Contract No. FDA 223-75-2004. Report No. SCOGS-65.

73. FASEB. (1977). Evaluation of the health aspects of sodium oleate and sodium palmitate as substances migrating to food from paper and paperboard used in food packaging. DHEW Contract No. FDA 223-75-2004. Report No. SCOGS-86. NTIS PB-276 414.

74. JOHNSON, V., CARLSON, A.)., and JOHNSON, A. (1933). Studies on the physiological action of glycerin on the animal organism. Am.). Physiol. 103(3), 517-534. In: Informatics, Ref. 69.

75. HOLCK, H.G.O. (1937). Glycerin, ethylene glycol, propylene glycol and diethylene glycol. Report on feeding experiments with rats. JAMA 109, 1517-1520. In: Informatics, Ref. 69.

76. FISCHER, L., KOPF, R., LOESER, A., and MEYER, G. (1949). Chemical structure and pharmacological effects of glycols, particularly 1 ,3-butylene glycol. Z. Ges. Exp. Med. 115, 22-39. In: Informatics, Ref. 69.

77. LOESER, A., BORNMANN, G., GROSSKINSKY, L., HESS, G., KOPF, R., RITIER, K., SCHMITZ, A., STU ERMER, E., and WEGENER, H. (1954). Diethylene glycol. Pharmacology and toxicology of polyglycols. Naunyn-Schmiedebergs Arch. Expt. Pathol. Pharmakol. 221, 14-33. In: Informatics, Ref. 69.

78. STOEWSAND, G.S., DYMSZA, H.A., SWIFT, S.M., MEHLMAN, M.A., and THERRIAULT, D.G. (1966). Effect of feeding polynyaric alcohols on tissue lipids and the resistance of rats to extreme cold. ). Nutr. 89(4), 414-418. In: Informatics, Ref. 69.

79. STOEWSAND, G.S., and DYMSZA, H.A. (1967). Synthetic sources of calories in the diets of rats and dogs. Proc. 7th Int. Congr. Nutr., 1966. 4, 1082-1087. In: Informatics, Ref. 69.

80. STAPLES, R., MISHER, A., and WARDELL,). Jr. (1967). Gastrointestinal irritant effect of glycerin as compared with sorbitol and propylene glycol in rats and dogs. j. Pharm. Sci. 56, 398-400. In: FASEB, Ref. 30.

81. OSTWALD, R. (1962). Glycerol intake, blood cholesterol level, and anemia in the guinea pig and rabbit. Proc. Soc. Exp. Bioi. Med. 111, 632-634. In: Informatics, Ref. 69.

82. BORNMANN, G. (1955). Physiological properties of glycols and their toxicity. Arzneimittei-Forsch. 4, 613-616. In: Informatics, Ref. 69.

83. KOPF, R., LOESER, A., and MEYER, G. (1951). Biologic actions of 1 ,2,4-buta-netriol and 1 ,2,3,-propanetriol (glycerin). Arch. Exp. Pathol. Pharmakol. 212, 405-415. In: Informatics, Ref. 69.

84. GUERRANT, N.B., SHITLOCK, G.P., WOLFF, M.L., and DUTCHER, R.A. (1947). Response of rats to diets containing varying amounts of glycerin and propylene glycol. Bull. Natl. Formulary Comm. 15, 205-229. In: Informatics, Ref. 69.

85. HINE, C.H., ANDERSON, H.H., MOON, H.D., DUNLAMP, M.K., and MORSE, M.S. (1953). Comparative toxicity of synthetic and natural glycerin. Arch. Indus!. Hyg. Occup. Med. 7(4), 282-291. In: Informatics, Ref. 69.

86. ANDERSON, R.C., HARRIS, P.N., and CHEN, K.K. (1950). Toxicologic studies on synthetic glycerin.). Am. Pharm. A. (Scient. Ed.) 39, 583-585. In: Informatics, Ref. 69.

87. ATLAS CHEMICAL INDUSTRIES. (1969). Glycerin: A two-year feeding study in rats. Report No. 11392. FDA Food Additive Petition No. 925. In: Informatics, Ref. 69; FASEB, Ref. 30.

88. FLESCH, P. (1953). Studies on the mode of action of vitamin A.). Invest. Dermatol. 21, 421-434. In: FASEB, Ref. 73.

89. SUNDE, M.L. (1956). The effect of fats and fatty acids in chick rations. Poultry Sci. 35, 362-368. In: FASEB, Ref. 73.

90. ROBERTSON, T.B., DAWBARN, M.C., THOMAS, R.G., WALTERS, ).W., and WILSON, ).D.O. (1933). Experiments on the growth and longevity of the white mouse. I. The influence of injections of thorium oleate in oleic acid, and of oleic acid alone, on growth and longevity. Aust. ). Exp. Bioi. Med. Sci. 11, 99-108.

91. CARROLL, K.K., and NOBLE, R.L. (1957). Influence of a dietary supplement of erucic acid and other fatty acids on fertility in the rat: Sterility caused by erucic acid. Can. j. Biochem. Physiol. 35, 1093-1105. In: FASEB, Ref. 73.

92. SZEPSENWOL, ). (1969). Brain nerve cell tumors in mice on diets supplemented with various lipids. Pathol. Microbiol. 34, 1-9.

93. SZEPSENWOL, ). (1978). Gastrointestinal tumors in mice of three strains maintained on fat-enriched diets. Oncology 35(4), 143-152.

94. KATO, A., ANDO, K., SUZUKI, S., TAMURA, G., and ARIMA, K. (1969). Antitumor activity of monoglycerides and other esters of fatty acids. ). Antibiot. (Tokyo). 22(2), 83-84.

95. CTFA. (January 10, 1977). Submission of unpublished data by CTFA. Human dermal irritation study on 15 percent and 30 percent aqueous solutions of Glyceryl Oleate using a single insult occlusive patch test. (2-47-16).*


ASSESSMENT: GLYCERYLOLEATE 413

96. CTFA. (August 11, 1983). Submission of unpublished data by CTFA. Human dermal irritation study on a fragrance preparation containing 19.0 percent Glyceryl Oleate. (2-47-2).*

97. LANMAN, B.M. (April 21-23, 1968). ]oint Conference of Cosmetic Sciences. Washington, D.C. 98. PHILLIPS, l., STEINBERG, M., MAIBACH, H., and AKERS, W. (1972). Toxicol. Appl. Pharmacal. 21,

369-382. 99. HILL TOP RESEARCH. (November 16, 1981). Submission of unpublished data by CTFA. Human cumula

tive dermal irritation study on a sunscreen formulation containing 5 percent Glyceryl Oleate. (2-47-13). * 100. FOOD AND DRUG RESEARCH LABORATORIES (FDRL). (April 12, 1973). Submission of unpublished

data by CTFA. Repeated insult patch test on a 15 percent aqueous solution of Glyercyl Oleate. (2-47-17). • 101. FDRL. (1981 ). Submission of unpublished data by CTFA. Human photoallergy, phototoxicity and primary

irritation/sensitization study on a sunscreen formulation containing 5 percent Glyceryl Oleate. (2-47-12) .•


Final Report of the ·Amended Safety Assessment of Glyceryllaurate, Glyceryllaurate SE, Glyceryl Laurate/Oieate, Glyceryl Adipate, Glyceryl Alginate, Glyceryl Arachidate, Glyceryl Arachidonate, Glyceryl Behenate, Glyceryl Caprate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Citrate/lactate/Linoleate/Oieate, Glyceryl Cocoate, Glyceryl Collagenate, Glyceryl Erucate, Glyceryl Hydrogenated Rosinate, Glyceryl Hydrogenated Soyate, Glyceryl Hydroxystearate, Glyceryl lsopalmitate, Glyceryl lsostearate, Glyceryl lsostearate/Myristate, G lyceryl lsostearates, G lyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Montanate, Glyceryl Myristate, Glyceryl lsotridecanoate/Stearate/ Adipate, Glyceryl Oleate SE, Glyceryl Oleate/Eiaidate, Glyceryl Palmitate, Glyceryl Palmitate/Stearate, Glyceryl Palmitoleate, Glyceryl Pentadecanoate, Glyceryl Polyacrylate, Glyceryl Rosinate, Glyceryl Sesquioleate, Glyceryi/Sorbitol Oleate/Hydroxystearate, Glyceryl Stearate/ Acetate, Glyceryl Stearate/Maleate, Glyceryl Tallowate, Glyceryl Thiopropionate, and Glyceryl Undecylenate1

The safety of 43 glyccryl monocsters listed as cosmetic ingredients was reviewed in a safety assessment completed in 2000. Additional safety test data pertaining to Glyceryl Rosinate and Glyceryl Hydrogenated Rosinate were received and served as the basis for this amended report. Glyceryl monoesters are used mostly as skinconditioning agents-emollients and/or surfactant-emulsifying

Received 12 February 2004; accepted 4 June 2004. 1 Reviewed by the Cosmetic Ingredient Review Expert Panel. This report

was prepared by Wilbur Johnson, Jr., Senior Scientific Analyst and Writer. Address correspondence to Wilbur Johnson, Jr., 1101 17th Street, NW, Suite 310, Washington, DC 20036, USA.

agents in cosmetics. The following 20 glyceryl monoesters are currently reported to be used in cosmetics: Glyceryl Laurate, Glyceryl Alginate, Glyceryl Arachidonate, Glyceryl Behenate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Cocoate, Glyceryl Erucate, Glyceryl Hydroxystearate, Glyceryl lsostearate, Glyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Myristate, Glyceryl Oleate/Elaidate, Glyceryl Palmitate, Glyceryl Polyacrylate, Glyceryl Rosinate, Glyceryl Stearate/Acetate, and Glyceryl Undecylenate. Concentration of use data received from the cosmetics industry in 1999 indicate that Glyceryl Monoesters are used at concentrations up to 12% in cosmetic products. Glyceryl Monoesters are not pure monoesters, but are mostly mixtures with mono-, di-, and tri-esters. The purity of commercial and conventional Monoglyceride (Giyceryl Monoester) is a minimum of 90%. Glyceryl Monoesters (monoglycerides) are metabolized to

International Journal of Toxicology, 23(Suppl. 2):55-94, 2004 Copyright © Cosmetic Ingredient Review ISSN: 1091-5818 print /1092-874X online DOl: 10.1080110915810490499064 55



free fatty acids and glycerol, both of which are available for the resynthesis of triglycerides. Glyceryl Laurate enhanced the penetration of drugs through cadaverous skin and hairless rat skin in vitro and' has been described as having a wide spectrum of antimicrobial activity. A low-grade irritant response was observed following inhalation of an aerosol containing 10% Glyceryl Laurate by test animals. Glyceryl monoesters have little acute or short-term toxicity in animals, and no toxicity was noted following chronic administration of a mixture consisting mostly of glyceryl di- and monoesters. Glyceryl Laurate did have strong hemolytic activity in an in vitro assay using sheep erythrocytes. Glyceryl Lam·ate, Glyceryl Isostearate, or Glyceryl Citrate!Lactate/Linoleate/Oleate were not classified as ocular irritants in rabbits. Undiluted glyceryl monoesters may produce minor skin irritation, especially in abraded skin, but in general these ingredients are not irritating at concentrations used in cosmetics. Glyceryl monoesters are not sensitizers, except that Glyceryl Rosinate and Hydrogenated Glyceryl Rosinate may contain residual rosin, which can cause allergic reactions. These ingredients are not photosensitizers. Glyceryl Citrate!Lactate!Linoleate/Oieate was not mutagenic in the Ames test system. Glyceryl Laurate exhibited antitumor activity and Glyceryl Stearate was negative in a tumor promotion assay. At concentrations higher than used in cosmetics, Glyceryl Laurate did cause moderate erythema in human repeat-insult patch test (RIPT) studies, but the other glyceryl monoesters tested failed to produce any significant positive reactions. Glyceryl Rosinate was irritating to animal skin at 50%, but did not produce sensitization in clinical tests at concentrations up to 10% and covered with semioccluded patches. There is reported use of Glyceryl Rosinate at 12% in mascara, which is somewhat higher than the concentration in the clinical testing. It was reasoned that the available data do support the safety of this use because there would be minimal contact with the skin and no occlusion. The safety of Arachidonic Acid was not documented and substantiated for cosmetic product use in an earlier safety assessment and those same safety questions apply to Glyceryl Arachidonate. Based on these data, the Cosmetic Ingredient Review (CIR) Expert Panel found that these glyceryl monoesters are safe as cosmetic ingredients in the present practices of use and concentration: except that the available data are insufficient to support the safety of Glyceryl Arachidonate. Additional data needed to support the safety of Glyceryl Arachidonate include (1) dermal absorption data; and, based on the results ofthe absorption studies, there may be a need for (2) immunomodulatory data; (3) carcinogenicity and photocarcinogenicity data; and ( 4) human irritation, sensitization, and photosensitization data.

INTRODUCTION Glyceryl monoesters are a group of ingredients comprising

esters of glycerin and assorted fatty acids or fatty acid derivatives. The 43 glyceryl monoesters listed in the International Cosmetic Ingredient Dictionary and Handbook (Pepe et al. 2002), which have uses in a wide variety of cosmetic products, mostly as conditioning agents, are included in this safety assessment. A final safety assessment of glyceryl monoesters was updated with additional safety test data for Glyceryl Rosinate and Glyceryl Hydrogenated Rosinate and an amended conclusion was reached.

Only 16 of the 43 ingredients were reported to the U.S. Food and Drug Administration (FDA) by industry as being used in cosmetics, but data received directly from industry indicate that

an additional4 ingredients are being used in cosmetics. If ingredients that are cunently not used were to be used in the future, the Cosmetic Ingredient Review (CIR) Expert Panel expects that the types of products and the concentrations used w<;mld be similar to those in current use.

Safety test data are available for only a limited number of ingredients. The CIR Expert Panel also considered safety assessments of related ingredients to be relevant. These include the earlier safety assessments ofGlyceryl Stearate and Glyceryl Stearate SE (Elder 1982), Glyceryl Oleate (Elder 1986), and Arachidonic Acid (Andersen 1993).

CHEMISTRY

Chemical and Physical Properties The glyceryl monoesters of fatty acids are primarily white to

yellow oils or oily waxes with faint fatty odors. These substances are not pure monoesters, but are mixtures with mono-, di-, and tri-ester contents of approximately 4:4:2 (Unichema International 1997b). Danisco Ingredients (1999c, 1999d) guarantees that the purity of their commercial and conventional Monoglyceride is a minimum of 90%.

The octanol/water partition coefficient (K0 w) is normally a measured value defined as the ratio of a chemical's concentration in the octanol phase to its concentration in the aqueous phase of a two-phase octanol/water system. The partition coefficient is normally represented by its logw value.

The octanol/water partition coefficient may be calculated. One method for calculating log(Kow) involves the use of fragment constants (Leo, Hansch, and Elkins 1971; Lyman, Reehl, and Rosenblatt 1982). The development of a method for calculation of log(K0 w) for glycerol monoesters is based on the known values of glycerol monoacetate and glycerol monobutyrate. Knowing these values, the fragment-constant of the glycerol-ester part can be calculated. From this value, the log(K0 w) of any glycerol monoester can be calculated using the chain-length and the number of double bonds (DB) of the acid part.

Physical properties of glyceryl monoesters are listed in Table 1.

These ingredients may be supplied as trade mixtures. The physical properties of one such trade mixture (50% Gylceryl Rosinate with 50% octyldecyl myristate) are shown in Table 2.

Further descriptions of the ingredients in this safety assessment follow.

Glyceryl Laurate (CAS nos. 142-18-7 and 27215-38-9) is the monoester of glycerin and lauric acid that conforms generally to the formula (Pepe, Wenninger, and McEwen 2002):

0 OH

II I CHs(CH2)1 oCOCH2CHCH2

I OH


Property

Form

Solubility

Odor

Molecular weight Melting point

Dropping point

Density pH

Hydroxyl value Iodine value

Iodine color Saponification value

Acid value

UV absorption

UV absorption

UV absorption

Form Solubility

Iodine value Iodine color Saponification value Acid value

GL YCERYL MONOESTERS

TABLE 1 Physical properties of Glyceryl Monoesters

Description

Glyceryl Laurate Cream-colored paste White crystalline White to cream-colored powder Off-white pellets Dispersable in water; soluble in methanol, ethanol, toluene,

naphtha, mineral oil, cottonseed oil, and ethyl acetate Practically insoluble in water; hardly soluble to readily soluble

in acetone, diethyl ether, and heptane Faint Faint, fatty odor 274.4 23-27°C

0.98 8.0-8.6 (25°C for 5% aqueous dispersion) 4-5 (1 0% in methanol/water 1 : 1) 395 5-8 2% max. (based on h)

<1 3 mg/1 00 ml max. (based on h) 200-206 195-205 mg KOH/g

205 3 mg KOH/g max. 3% max. Amax at 238 nm; Amin at 295 nm

Glyceryl Behenate Amax at 238 nm; Amin at 288 nm and 290 nm

Glyceryl Caprate Amax at 238 nm; Amin at 287 nm and 291 nm

Glyceryl Caprylate White crystalline Practically insoluble in water; hardly soluble to readily soluble

in various water/ethanol mixtures; readily soluble in acetone, diethyl ether, and heptane

1 g/100 g max. (based on h) 3 mg/100 ml max. (based on I2)

245-265 mg KOH/g 3 mg KOH/g max.

57

Reference '

Lewis 1993 Htils America, Inc., no date Henkel KgaA 1996 Danisco Ingredients 1996 Lewis 1993

Htils America, Inc., no date

Lewis 1993 Hi.ils America, Inc., no date Kabara 1984 Scientific & Technical

Information Network (STN) International 1997

Hi.ils America, Inc., no date Henkel KgaA 1996 Htils America, Inc., no date Henkel KgaA 1996 Lewis 1993 Lewis 1993 Htils America, Inc., no date Danisco Ingredients 1996 Lewis 1993 Htils America, Inc., no date Henkel KgaA 1996 Danisco Ingredients 1996 Hi.ils America, Inc., no date STN International 1997 Hi.ils America, Inc., no date Henkel KgaA 1996 Danisco Ingredients 1996 Hi.ils America, Inc., no date Henkel KgaA 1996 Danisco Ingredients 1999e

Danisco Ingredients 1999e


Hi.ils America, Inc., no date Hi.ils America, Inc., no date

Hi.ils America, Inc., no date Hi.ils America, Inc., no date Hi.ils America, Inc., no date Hi.ils America, Inc., no date

(Continued on next page)


58

'Property

UV absorption

UV absorption

Form Odor pH Saponification value Acid value

Form Solubility

Odor Melting point Iodine value Iodine color Saponification value Acid value

Appearance Odor Solubility

Specific gravity at 20°C Boiling point %volatile by volume

Calculated Octanol/water partition coefficient (log(K0 w))

UV absorption

Form Odor Specific gravity at 20°C Refractive index at 20°C Viscosity at 20°C Hydroxyl value Iodine value Saponification value Acid value

Form

Solubility


TABLE 1 Physical properties of Glyceryl Monoesters (Continued)

Description

Amax at 238 nm; Amin at 295 nm

Glyceryl Caprylate/Caprate Amax at 238 nm; Amin at 295 nm

Glyceryl Citrate/Lactate!Linoleate/Oleate Viscous, yellowish liquid Odor likened to soya bean oil; neutral taste 6-7 (10% in water) 230-250 mg KOH/g 15 mg KOH/g max.

Glyceryl Cocoate White to slightly yellowish liquid Practically insoluble in water; hardly soluble to soluble in

variouys water/ethanol mixtures; readily soluble in acetone, soluble in diethyl ether, and hardly soluble in heptane

Odor likened to coconut oil 31-37°C 3 g/1 00 g max. (based on I2) 5 mg/100 ml max. (based on I2) 200-300 mg KOH/g 2 mg KOH/g max.

Glyceryl Collagenate Clear to hazy amber liquid Proteinaceous odor At 5%, soluble in water, glycerine, 40% aqueous alcohol,

sodium Iaury! sulfate, and cocamidopropyl betaine 1.2 215°C 80%

Glyceryl Erucate 8.61

Amax at 238 nm; Amin at 287 nm and 291 nm

Glyceryl Isostearate Crystals; color <6 on Gardner scale Faint 0.930 to 0.970 1.455 to 1.475 0.7 to 1.2 Pa 180-280 mg KOH/g <15 g/100 g (based on I2) 150-170 mg <4 mg KOH/g

Glyceryl Linoleate Crystals obtained from benzene as solvent Soft plastic Soluble in ether, benzene, and chloroform

Reference


Danisco Ingredie~ts 1999e

Hi.ils America, Inc., no date Hiils America, Inc., no date Hiils America, Inc., no date Hiils America, Inc., no date Hiils America, Inc., no date

Hiils America, Inc., no date Hiils America, Inc., no date

Hi.ils America, Inc., no date Hi.ils America, Inc., no date Hi.ils America, Inc., no date Hiils America, Inc., no date Hi.ils America, Inc., no date Hi.ils America, Inc., no date

Brooks Industries 1998 Brooks Industries 1998 Brooks Industries 1998

Brooks Industries 1998 Brooks Industries 1998 Brooks Industries 1998

Danisco Ingredients 1999a


Gattefosse 1998

Gattefosse 1998 Gattefosse 1998 Gattefosse 1998 Gattefosse 1998 Gattefosse 1998 Gattefosse 1998 Gattefosse 1998

Lide and Frederikse 1993 Danisco Ingredients 1996 Lide and Frederikse 1993



Property

Refractive index Molecular weight Melting point

Hydroxyl value Iodine value Saponification value UV absorption

UV absorption

UV absorption

Specific rotation Calculated Octanol/water

partition coefficient (log(Kow))

Molecular weight Melting point UV absorption

Form Dropping point Hydroxyl value Iodine value Saponification value Acid value UV absorption

UV absorption

UV absorption

UV absorption

Form Solubility

Odor Melting point pH Saponification value Acid value

GL YCER YL MONOESTERS

TABLE 1 Physical properties of Glyceryl Monoesters (Continued)

1.4758 at 20°C 354.53 14.SOC

Description

45°C (completely melted) 310 105 160 Amax at 238 nm; Amin at 270 nm

Glyceryl Myristate Amax at 238 nm; Amin at 293 nm

Glyceryl 0/eate/Elaidate Amax at 239 nm; Amin at 270 nm

Glyceryl Palmitate -4.37 (in pyrimidine) 6.38

330.51 71-72°C A.max at 238 nm; Amin at 295 nm

Glyceryl Palmitate/Lactate Off-white pellets sooc 160 <2 245-265 5 max. Amax at 239 nm; Amin at 287 nm

Glyceryl Palmitate/Stearate Amax at 238 nm; Amin at 295 nm

Glyceryl Palmitoleate Amax at 238 nm; Amin at 270 nm and 280 nm

Glyceryl Sesquioleate Amax at 239 nm

Glyceryl Stearate/Citrate White ivory-colored powder Well soluble in acetone; insoluble in alcohols and ethers;

sparingly soluble in ethanol; and turbid soluble in medium shain triglycerides and fatty oils

Neutral, fatty odor 59-63°C 10-30 (10% in water 1:1) 230-260 mg KOH/g 15-25 mg KOH/g max.

59

Reference '

Lide and Frederikse 1993 Lide and Frederikse 1993 Lide and Frederikse 1993 Danisco Ingredients 1996 Danisco Ingredients 1996 Danisco Ingredients 1996 Danisco Ingredients 1996 Danisco Ingredients 1999e



Lide and Frederikse 1993 Danisco Ingredients 1999a

Lide and Frederikse 1993 Lide and Frederikse 1993 Danisco Ingredients 1999e

Danisco Ingredients 1996 Danisco Ingredients 1996 Danisco Ingredients 1996 Danisco Ingredients 1996 Danisco Ingredients 1996 Danisco Ingredients 1996 Danisco Ingredients 1999e




Htils America, Inc., no date Htils America, Inc., no date

Hiils America, Inc., no date Htils America, Inc., no date Htils America, Inc., no date Htils America, Inc., no date Hiils America, Inc., no date



TABLE2 Physical properties of Purified Ester Gum-2-0ctyiDodecyl Myristate (Purified Ester Gum/M.O.D.), a trade mixture containing

SO% Glyceryl Rosinate and 50% Octyldecyl Myristate

Property Description Reference'

Appearance Viscous transparent light-brown liquid with almost no odor

Shin-Ei Chemical Company Ltd. 1998

Description Viscous liquid made up of purified ester gum dissolved in 2-octyl dodecyl myristate in a 50:50 ratio. Ester gum is a rosin ester whose main component is ester of abietic acid and glycerol

Cosmo Trends, no date

0.9625 to 0.9725 1.4930 to 1.4980

Specific Gravity (d~~) Refractive Index (n~0 ) Solubility Soluble in olive oil, castor oil, petrolatum, and liquid

paraffin. Insoluble in glycerin, water, and propylene glycol

U.S. Cosmetics Corporation 1998 U.S. Cosmetics Corporation 1998 Shin-Ei Chemical Company Ltd. 1998

Melting point Flash point Acid value Heavy metals (ppm) Arsenic (ppm) Moisture(%) Solid content (%) Percent volatile Volatile organic compounds Oxidation Stability Hazardous decomposition

products

No data available 272°C <12 <20 <2 <0.1 g 50±2 Almost none None identified Little tendency to oxidize Stable with almost no reactivity Almost none

According to Danisco Ingredients (1999c), two isomeric forms (a and {3) exist; the structure above is the a form. Glyceryl Laurate also has been described as a distilled monoglyceride that is made from edible vegetable fatty acids (mainly lauric acid) (Danisco Ingredients 1999c) as well as a molecular distillated lauric acid monoglyceride (Henkel KgaA 1994 ). Other names for this chemical include Dodecanoic Acid, 2,3-Dihydroxypropyl Ester; Dodecanoic Acid, Monoester with 1,2,3-Propanetriol; Glyceryl Monolaurate; and Lauricidin (Pepe, Wenninger, and McEwen 2002); Laurin, 1-Mono; alphaMonolaurin; 1-Giyceryl La urate; 1-Monododecanoylglycerol; 1-Monolaurin; Dodecanoic Acid alpha-Monoglyceride; Glycerin 1-Monolaurate; Glycerol alpha-Monolaurate; Glycerol 1-Laurate; Glycerol 1-Monolaurate; Glyceryl Monododecanoate; Glyceryl Monolaurate; Lauric Acid alpha-Monoglyceride; and Lauric Acid 1-Monoglyceride (Scientific & Technical Information Network [STN] Internationa11997).

Commercial Glyceryl Laurate consists of 90% monoester, free glycerol (maximum 4% ), and free fatty acid (maximum 1 %). Its fatty acid profile is as follows: C10 (maximum 10%), C12 (maximum 90%), and C14 (maximum 8%) (Kabara 1984).

Henkel KgaA (1996) confirmed the 90% monoester content of Glyceryl La urate and indicated that free glycerin is present at concentrations up to 2%.

Shin-Ei Chemical Company Ltd. 1998 U.S. Cosmetics Corporation 1998 U.S. Cosmetics Corporation 1998 U.S. Cosmetics Corporation 1998 U.S. Cosmetics Corporation 1998 U.S. Cosmetics Corporation 1998 U.S. Cosmetics Corporation 1998 Shin-Ei Chemical Company Ltd. 1998 Shin-Ei Chemical Company Ltd. 1998 Shin-Ei Chemical Company Ltd. 1998 Shin-Ei Chemical Company Ltd. 1998 Shin-Ei Chemical Company Ltd. 1998

I-li.ils America, Inc. (no date) states that Glyceryl La urate contains free glycerol ( 1% ), monoglycerides (95% ), diglycerides (2% ), and water (maximum 1% ).

Danisco Ingredients (1996) states that the composition of Glyceryl Lam·ate is as follows: monoester content (minimum 90% ), free glycerol (maximum 1% ), and free fatty acids (maximum 1.5%).

Glyceryl La urate SE is a self-emulsifying grade of Glyceryl Laurate that contains some sodium and/or potassium laurate (Pepe, Wenninger, and McEwen 2002).

Glyceryl Laurate/Oieate is the monoester of glycerin and a blend of lauric and oleic acids (Pepe, Wenninger, and McEwen 2002).

Glyceryl Adipate (CAS no. 26699-71-8) is the ester of glycerin and adipic acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

Hexanedioic Acid, Monoester with 1,2,3-Propanetriol is another name for this chemical (Pepe, Wenninger, and McEwen 2002).


GL YCERYL MONO ESTERS 61

Glyceryl Alginate is the ester of glycerin and alginic acid. Alginic Acid, Glyceryl Ester is anotper name for this chemical (Pepe, Wenninger, and McEwen 2002).

Glyceryl Arachidate (CAS nos. 30208-87-8 and 50906-68-8) is the ester of glycerin and arachidic acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

0 0

II II HOCH2CHCH20C(CH2)4COH

I OH

Other names for this chemical include 2,3-Dihydroxypropyl Eicosanoate; Eicosanoic Acid, 2,3-Dihydroxypropyl Ester; Eicosanoic Acid, Monoester with 1 ,2,3-Propanetriol; and Glyceryl Monoarachidate (Pepe, Wenninger, and McEwen 2002).

Glyceryl Arachidonate (CAS no. 35474-99-8) is the monoester of glycerin and arachidonic acid that conforms to the following formula (Wenninger et al. 2000):

Other names for this chemical include: Arachidonic Acid, Monoester with 1 ,2,3-Propanetriol; 2,3-Dihydroxypropyl 5,8,11,14-Eicosatetraenoate; 5,8,11,14-Eicosatetraenoic Acid, 2,3-Dihydroxypropyl Ester-; and Glyceryl Monoarachidonate (Pepe, Wenninger, and McEwen 2002).

Glyceryl Behenate (CAS nos. 6916-74-1 and 30233-64-8) is the monoester of glycerin and behenic acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

0

II CH 3(CH2h0COCH2CHCH20H

I OH

Other names for this chemical include 2,3-Dihydroxypropyl Docosanoate; Docosanoic Acid, 2,3-Dihydroxypropyl Ester; Docosanoic Acid, Monoester with 1 ,2,3-Propanetriol; and Glyceryl Monobehenate (Pepe, Wenninger, and McEwen 2002).

Glyceryl Caprate (CAS no. 26402-22-2) is the monoester of glycerin and capric acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

0

. II CH 3(CH2)8COCH2CHCH20H

I OH

Other names for this chemical include Decanoic Acid, Monoester with 1 ,2,3-Propanetriol and Glyceryl Monocaprate (Pepe, Wenninger, and McEwen 2002).

Glyceryl Caprylate (CAS no. 26402-26-6) is the monoester of glycerin and caprylic acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

It has a molecular weight of 218.29 (Budavari 1989). Other names for this chemical include Glyceryl Monocaprylate and Octanoic Acid, Monoester with 1 ,2,3-Propanetriol (Pepe, Wenninger, and McEwen 2002), and Monooctanoin (Budavari, 1989). The typical composition of Glyceryl Caprylate is described as follows: free glycerol (1% ), monoglycerides (90% ), diglycerides (7% ), triglycerides ( 1% ), and water (maximum 1%) (Hiils America, Inc., no date).

Glyceryl Caprylate/Caprate is a mixture of monoglycerides of caprylic and capric acids (Pepe, Wenninger, and McEwen 2002).

Glyceryl Citrate!Lactate!Linoleate/Oleate is the ester of glycerin and a blend of citric, lactic, linoleic and oleic acids (Pepe, Wenninger, and McEwen 2002). More specifically, it is a partially neutralized ester of mono- and diglycerides of unsaturated edible fatty acids with citric acid and lactic acid (Hiils America, Inc., no date).

Glyceryl Cocoate (CAS no. 61789-05-7) is the monoester of glycerin and coconut fatty acids that conforms to the following formula, where R represents the fatty acids derived from coconut oil (Pepe, Wenninger, and McEwen 2002):

More specifically, it is composed of partial glycerides (mono/di/triglycerides) of the saturated fatty acids of coconut oil. The chain length is Cw to C1s; the main component is C12 ,

as in coconut oil (Htils America, Inc., no date). Other names for this chemical include: Glycerides, Coconut Oil Mono-; Glycerol Mono Coconut Oil; Glyceryl Coconate; and Glyceryl Monococoate (Pepe, Wenninger, and McEwen 2002). The typical composition of Glyceryl Cocoate is described as follows: free glycerol (1 %), monoglycerides (45% ), diglycerides (35%), triglycerides (15% ), and water (maximum 1%) (Htils America, Inc., no date).

Glyceryl Collagenate is the ester of glycerin and collagen (q.v.) (Pepe, Wenninger, and McEwen 2002). It consists



of ~25% solids and its chemical structure, where R is an amino group typical of collagen, is included below (Brooks Industries 1998):

0 0

II II NH2CHCNHCHCOCH 2CHCH20H

I I I R R OH

Glyceryl Erucate (CAS no. 28063-42-5) is the monoester of glycerin and erucic acid that conforms generally to the following formula (Pepe, Wenninger, and McEwen 2002):

Other names for this chemical include Glyceryl Monoerucate and Erucic Acid, Monoester with 1 ,2,3-Propanetriol (Pepe, Wenninger, and McEwen 2002).

Glyceryl Hydrogenated Rosinate is the monoester of glycerin and hydrogenated mixed long chain acids derived from rosin (Pepe, Wenninger, and McEwen 2002). It also exists as a mixture of 50% Glyceryl Hydrogenated Rosinate and 50% Octyldodecyl Myristate (McEwen 2000).

Glyceryl Hydrogenated Soyate is the monoester of glycerin (q.v.) and hydrogenated mixed long chain acids derived from soy (Pepe, Wenninger, and McEwen 2002). According to Danisco Ingredients (1999c), this ingredient is a distilled monoglyceride made from edible, fully hydrogenated vegetable oil.

Glyceryl Hydroxystearate (CAS no. 1323-42-8) is the monoester of glycerin and hydroxystearic acid (q.v.) that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

Other names for this chemical are as follows: Glyceryl Hydroxystearate (1 ); Glyceryl Hydroxystearate (2); Glyceryl Monohydroxystearate; Hydroxystearic Acid, Monoester with Glycerol; and Stearic Acid, Hydroxy-, Monoester with Glycerol (Pepe, Wenninger, and McEwen 2002).

Glyceryl Isopalmitate is the monoester of glycerin and a branched chain 16-carbon aliphatic acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

Other names for this chemical include Isopalmitic Acid, 2,3-Dihydroxypropyl Ester and Isopalmitic Acid, Monoester with 1 ,2,3-Propanetriol (Pepe, Wenninger, and McEwen 2002).

Glyceryl Isostearate (CAS nos. 66085-00-5 and 61332-02-3) is the monoester of glycerin and isostearic acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

Other names for this chemical include Glyceryl Isostearate (1), Glyceryl Monoisostearate, and Isooctadecanoic Acid, Monoester with 1 ,2,3-Propanetriol (Pepe, Wenninger, and McEwen 2002).

Gattefosse s.a. (1998) described the composition of Glyceryl Isostearate as containing 1-monoglycerides (>30%), free glycerol ( <7% ), and water ( <0.50% ).

Glyceryl Isostearate/Myristate is the monoester of glycerin and a blend of isostearic and myristic acids. Glyceryl Monisostearate Monomyristate is another name for this chemical (Pepe, Wenninger, and McEwen 2002).

Glyceryl lsostearates is a mixture of the mono-, di-, and triesters of glycerin and isostearic acid. This chemical is also known as Glyceryl Isostearate (2) (Pepe, Wenninger, and McEwen 2002).

Glyceryl Isotridecanote/Stearate/Adipate is the ester of glycerin (q.v.) and a blend of isotridecanoic acid, stearic acid, and adipic acid (Pepe, Wenninger, and McEwen 2002).

Glyceryl Lanolate is the monoester of glycerin and lanolin acid (q.v.). Other names for this chemical include Glyceryl Monolanolate and Lanolin Acid, Monoester with 1,2,3-Propanetriol (Pepe, Wenninger, and McEwen 2002).

Glyceryl Linoleate (CAS no. 2277-28-3) is the monoester of glycerin and linoleic acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002).

CH3(CH2)4CH

II CHCH2~H ~

CH(C~)7C- OCH2~HCH20H

OH

Other names for this chemical include 2,3-Dihydroxypropyl 9, 12-0ctadecadienoate; Glyceryl Monolinoleate; Linoleic Acid,


GL YCERYL MONOESTERS 63

Monoester with 1 ,2,3-Propanetriol; Monolinolein; 9,12-0ctadecadienoic Acid, 2,3-Dihydroxypropyl Ester; and 9,12-0ctadecadienoic Acid, Monoester' with 1 ,2,3-Propanetriol (Pepe, Wenninger, and McEwen 2002).

Danisco Ingredients· (1996) s.tated that the composition of Glyceryl Linoleate is as follows: monoester content (minimum 90%); free glycerol (maximum 1 %); free fatty acid (maximum 1.5% ); butyl hydroxy anisole (BHA), as antioxidant (maximum 200 ppm); and citric acid, as antioxidant (maximum 200 ppm) (Note: Citric acid is dissolved in propylene glycol.)

Glyceryl Linolenate (CAS no. 18465-99-1) is the monoester of glycerin and linolenic acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

According to Danisco Ingredients (1999c), Glyceryl Linolenate is a distilled monoglyceride that is made from edible, refined sunflower oil. Other names for Glyceryl Linolenate include 2,3-Dihydroxypropyl 9, 12, 15-0ctadecatrienoate; Glyceryl monolinolenate; Linolenic Acid, Monoester with 1 ,2,3-Propanetriol; and 9,12,15-0ctadecatrienoic Acid, 2,3-Dihydroxypropyl Ester (Pepe, Wenninger, and McEwen 2002).

Glyceryl Montanate (CAS no. 68476-38-0) is the monoester of glycerin and montan acid wax. Other names for this chemical include 2,3-Dihydroxypropyl Octacosanoic Acid; Glycerides, Montan-Wax; Montan-Wax Fatty Acids, Glyceryl Esters; and Octacosanoic Acid, 2,3-Dihydroxypropyl Ester (Pepe, Wenninger, and McEwen 2002).

Glyceryl Myristate (CAS nos. 589-68-4 and 27214-38-6) is the monoester of glycerin and myristic acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

0

II CH3(CH2)12COCH2CHCH20H

I OH

According to Danisco Ingredients (1999c), it is a distilled monoglyceride that is made from vegetable fatty acids (mainly myristic acid). Other names for this chemical include: Glyceryl Monomyristate; Moncimyristin; and Tetradecanoic Acid, Monoester with 1,2,3-Propanetriol (Pepe, Wenninger, and McEwen 2002).

Glyceryl Oleate SE is a self-emulsifying grade of Glyceryl Oleate'(q.v.) that contains some sodium and/or potassium oleate (Pepe, Wenninger, and McEwen 2002).

Glyceryl Oleate/Elaidate is a mixture of monoglycerides of oleic and elaidic acids (Pepe, Wenninger, and McEwen 2002). According to Danisco Ingredients (1999c), it is a distilled monoglyceride made from edible, partially hydrogenated soya bean oil.

Glyceryl Palmitate (CAS no. 26657-96-5) is the monoester of glycerin and palmitic acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

Other names for this chemical include: Glyceryl Monopalmitate; Hexadecanoic Acid, 2,3-Dihydroxypropyl Ester; and Hexadecanoic Acid, Monoester with 1 ,2,3-Propanetriol; Hexadecanoic acid a-monoglyceride; Palmiric Acid Monoglyceride; Palmitin, mono-; and Palmitin, 1-mono- (Pepe, Wenninger, and McEwen 2002).

Glyceryl Palmitate/Stearate (CAS no. 68002-71-1) is the monoester of glycerin and a blend of palmitic and stearic acids (Pepe, Wenninger, and McEwen 2002). According to Danisco Ingredients (1999c ), it is a distilled monoglyceride made from edible, fully hydrogenated lard or tallow.

Glyceryl Palmitoleate is the monoester of glycerin and palmitoleic acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

According to Danisco Ingredients (1999c ), it is a distilled monoglyceride that is made from edible, refined palm oil. Other names for this chemical include Glyceryl Monopalmitoleate; Palmitoleic Acid, 2,3-Dihydroxypropyl Ester; and Palmitoleic Acid, Monoester with 1 ,2,3-Propanetriol (Pepe, Wenninger, and McEwen 2002).

Glyceryl Pentadecanoate is the monoester of glycerin and pentadecanoic acid that conforms to the following formula, where RCO- represents the pentadecanoyl radical (Pepe, Wenninger, and McEwen 2002):

0

II RCOCH2CHCH20H

I OH



Another name for this chemical is 2,3-dihydroxypropanepentadecanoate (Pepe, Wenninger, and McEwen 2002).

Glyceryl Polyacrylate is the ester of glycerin (q.v.) and polyacrylic acid (q.v.) (Pepe, Wenninger, and McEwen 2002).

Glyceryl Rosinate (CAS no. 8050-31-5) is the monoester of glycerin and mixed long chain acids derived from rosin (q.v.). Glycerin monorosinate and resin acids and rosin acids, esters with glycerin are two other names for this chemical (Pepe, Wenninger, and McEwen 2002).

In an FDA review of safety (FDA 1988), rosin is the residue remaining when the volatile oil is distilled from turpentine or a product of the distillation, solvent extraction, or both, of the stumps or fallen trees of various species of Pinus. Abietic acid and dehydroabietic acid are the main components that have been identified. Rosin nomenclature is based on the source from which it is obtained. Thus, rosin obtained .from offical (gum) turpentine is known as gum rosin. Wood rosin is rosin distilled or extracted out of the wood of stumps of fallen trees. These rosins differ in color, % resene, and in the softening point.

Glyceryl Rosinate is supplied as a trade mixture that is known as Purified Ester Gum-2-0cty!Dodecyl Myristate (Purified Ester Gum/M.O.D.) (US Cosmetics Corporation, no date). Purified Ester Gum-2-0cty!Dodecyl Myristate consists of 50% Glyceryl Rosinate and 50% octyldodecyl myristate (Shin-Ei Chemical Company Ltd. 1998), and properties of this trade mixture are presented in Table 2. The structural formula for Purified Ester Gum-2-0ctyldodecyl Myristate is indicated below (US Cosmetics Corporation, no date):

Where R =

Glyceryl Sesquioleate is a mixture of mono- and di-esters of glycerin and oleic acid (Pepe, Wenninger, and McEwen 2002).

Glycery !/Sorbitol Oleate/Hydroxystearate is the mixed esterification product of glycerin and sorbitol with hydroxystearic and oleic acids (Pepe, Wenninger, and McEwen 2002).

Glyceryl Stearate/Acetate is the monoester of glycerin and a blend of stearic and acetic acids. Glyceryl monostearate monoacetate is another name for this chemical (Pepe, Wenninger, and McEwen 2002).

Glyceryl Stearate/Maleate is the monoester of glycerin and a blend of stearic and maleic acids (Pepe, Wenninger, and McEwen 2002).

Glyceryl Tallowate is the monoester of glyc~rin and tallow fatty acids that conforms to the following formula, where ReOrepresents the fatty acids derived from tallow (Pepe, Wenninger, and McEwen 2002):

Another name for this chemical is glyceryl monotallowate (Pepe, Wenninger, and McEwen 2002).

Glyceryl Thiopropionate is the organic compound that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

Glyceryl Undecylenate is the ester of glycerin and undecylenic acid that conforms to the following formula (Pepe, Wenninger, and McEwen 2002):

Other names for this chemical are glyceryl monoundecylenate and undecylenic acid, monoester with 1,2,3-propanetriol (Pepe, Wenninger, and McEwen 2002).

Octanoi/Water Partition Coefficients Measured octanol/water partition coefficients were not avail

able. Calculated values received from one supplier are given in Table 3.

Analytical Methods Glyceryl Laurate has been analyzed by thin-layer chromatog

raphy, gas-liquid chromatography (Kabara 1984), reverse-phase high performance liquid chromatography (HPLC) (Maruyama and Yonese 1986; Takano and Kondoh 1987), capillary supercritical fluid chromatography (Giron, Link, and Bouissel1992), and ultraviolet (UV) spectral analysis-results are summarized in Table 1 (Danisco Ingredients 1999e).


GL YCER YL MONOESTERS 65

TABLE3 ' ,,

Calculated octanol/water partition coefficients of Glyceryl Monoesters (Danisco Ingredients 1999a)

Ingredient

Glyceryl Laurate Glyceryl Oleate Glyceryl Behenate Glyceryl Caprate Glyceryl Caprylate Glyceryl Erucate Glyceryl Linoleate Glyceryl Linolenate Glyceryl Myristate Glyceryl Elaidate Glyceryl Palmitate Glyceryl Stearate Glyceryl Palmitoleate Glyceryl Hydroxystearate

Methods of Production

log (Ko/w)

4.22 7.00 9.62 3.14 2.06 8.61 5.44 4.60 5.30 6.45 6.38 7.69 5.37 5.59

According to Kabara (1984 ), industrial monoglycerides can be prepared by the direct esterification of glycerol with a fatty acid, yielding mixtures of mono-, di-, and triglycerides, depending on the molar ratio of the reactants. In the case of Glyceryl Laurate, the lauric acid that is used for esterification is generally derived from the oil of various species of palm, such as coconut and babassu. The glycerolysis of fats and oils, a transesterification reaction, is a common commercial method for the preparation of monoglycerides.

Glyceryl Collagenate is produced via the esterification of hydrolyZed collagen with United States Pharmacopeia (USP) glycerine 99% (Brooks Industries 1998).

Glyceryl Rosinate is contained in a trade mixture of purified ester gum-2-octyldodecyl myristate (containing 50% Glyceryl Rosinate and 50% octyldecyl myritstate), which is prepared by mixing (with heat) purified ester gum and 2-octyldodecyl myristate in a I: I ratio. The mixture is then subjected to purificatibn processes such as decoloration, dehydration, deodorization and filtration (US Cosmetics Corporation, no date).

Composition/Impurities Data on the chemical characterization of Glyceryl

Monoesters are shown in Table 4. Danisco Ingredients ( 1999d), indicated that a content of 3.5%

to 4% total (mono)glycerol diester's are common in the manufacturing of distilled monoglyceride's. In the manufacturing of any less than 90% monoglyceride (commonly referred to as mono-diglycerides, albeit the INCI name does not differentiate), the content of (mono)glycerol diester's is higher. Because there is some diglycerol then there is also a "family" of diglycerol esters (mono- and di-esters). Consequently one can read from the tabulation of "impurities" for instance for a main product like DIMODAN PM [Glyceryl Palmitate/Stearate], that out of approximately 4% (mono )glycerol diester's, then approximately 29% of this is 1,2 (mono )glycerol diester. This would correspond to an approximate concentration of 1,2 (mono)glycerol diester of 1.2%.

Glyceryl La urate contains ash (maximum 0.1%) (Hiils America, Inc., no date) and heavy metals, as Pb ( <10 mg/kg) (Danisco Ingredients 1996).

TABLE4 Impurities data on Glyceryl Monoesters (Danisco Ingredients 1999c, 1999d)

Ratio of 1 ,2-(mono )glycerol %free % dig1ycerol diester to total

Ingredients %glycerol % diglycerol fatty acid monoester (mono )glycerol diester

Glyceryl Laurate 0.07 0.24 0.16 24.8 Glyceryl Behenate 0.03 0.09 0.15 29.1 Glyceryl Caprate 1.03 0.43 0.06 21.0 Glycery I Caprylate/Caprate 5.37 34.3 Glyceryl Linolenate 0.03 0.15 0.11 35.8 Glyceryl Myristate 0.30 0.57 0.14 27.8 Glyceryl Oleate/Elaidate 0.03 0.12 0.35 33.4 Glyceryl Palmitate 0.03 0.06 0.79 10.6 Glyceryl Palmitate/Lactate 0.04 0.82 30.6 Glyceryl Palmitate/Stearate 0.27 0.10 0.98 0.28 29.2 Glyceryl Palmitoleate 0.04 0.14 0.41 27.3 Glyceryl Sesquioleate 0.24 0.42 30.5 Glyceryl Hydrogenated 0.60 0.28 0.11 26.0

Soy ate


66 COSME1'Ic INGREDIENT REVIEW

Glyceryl Caprylate and Glyceryl Cocoate contain ash at a maximum concentration of 0.1% (Hiils America, Inc., no date).

Glyceryl Collagenate contains a low level of sodium chloride, byproduct of the production process (Brooks Industries I 998). It also contains nonvolatile matter (25% to 31%) and moisture (67% to 73%).

Glyceryl Hydrogenated Soyate specifications, given by Danisco Ingredients (1999c), include: monoester content (minimum 90%), iodine value (maximum 2%), free glycerol (maximum I%), free fatty acids (maximum 1.5% ), dropping point (~72°C), and form (beads). Specifications for heavy metal impurities include: arsenic (As) (11,1aximum 3 mg/kg), lead (Pb) (maximum 5 mg/kg), mercury (Hg) (maximum 1 mg/kg), Cadmium (Cd) (maximum I mg/kg), and heavy metals (as Pb) (maximum 10 mg/kg).

Glyceryl Isostearate impurities are as follows: alkaline impurities ( <80 ppm NaOH), sulfated ash content ( <0.2% ), and heavy metals ( < 10 ppm Pb) (Gattefo~se s.a. 1998).

Glyceryl Linoleate contains heavy metals (as Pb) at< 10 mg/ kg (Danisco Ingredients 1996).

Glyceryl Linolenate specifications, given by Danisco Ingredients (1999c), include monoester content (minimum 90%), iodine value (approximately 10% ), free glycerol (maximum 1% ), free fatty acids (maximum 1.5%), temperature at which completely melted (~45°C), and form (paste). Specifications for heavy metal impurities are as follows: arsenic (As) (maximum 3 mg/kg), lead (Pb) (maximum 5 mg/kg), mercury (Hg) (maximum 1 mg/kg), cadmium (Cd) (maximum 1 mg/kg), and heavy metals (as Pb) (maximum 10 mg/kg). Glyceryl Linolenate also contains the antioxidants, BHA (maximum 200 ppm) and citric acid dissolved in propylene glycol (maximum 200 ppm).

Glyceryl Myristate specifications, given by Danisco Ingredients (1999c), include monoester content (minimum 90%), free glycerol (maximum 1 %), and free fatty acids (maximum 1.5%). The typical value for heavy metals (as Pb) in Glyceryl Myristate is <10 mg/kg.

Glyceryl Oleate/Eiaidate specifications, given by Danisco Ingredients (1999c), include arsenic (As) (maximum 3 mg/kg), lead (Pb) (maximum 5 mg/kg), mercury (Hg) (maximum 1 mg/kg), cadmium (Cd) (maximum 1 mg/kg), and heavy metals (as Pb) (maximum 10 mg/kg). It also contains the antioxidants, citric acid ester (maximum 300 ppm), a-tocopherol (maximum 200 ppm), and ascorbyl palmitate (maximum 200 ppm).

Glyceryl Palmitate/Stearate specifications, given by Danisco Ingredients (1999c), include monoester content (minimum 90% ), iodine value (maximum 2% ), free glycerol (maximum 1% ), free fatty acids (maximum1.5% ), dropping point (~70°C), and form (beads). Specifications for heavy metal impurities are as follows: arsenic (As) (maximum 3 mg/kg), lead (Pb) (maximum 5 mg/kg), mercury (Hg) (maximum 1 mg/kg), cadmium (Cd) (maximum I mg/kg), and heavy metals (as Pb) (maximum 10 mg/kg).

Glyceryl Palmitoleate specifications, given by Danisco Ingredients ( 1999c ), include monoester content (minimum 90% ),

iodine value ( ~40), free glycerol (maximum 1% ), free fatty acids (maximum 1.5% ), dropping point ( ~60°C), and form (plastic). Specifications for heavy metal impurities are as follows: arsenic (As) (maximum 3 mg/kg), lead (Pb) (maximum 5 mg/kg), mercury (Hg) (maximum 1 mg/kg), cadmium (Cd) (maximum 1 mg/kg), and heavy metals (as Pb) (maximum I 0 mg/kg). Glyceryl Palmitoleate also contains the antioxidants, BHA (maximum 200 ppm) and citric acid dissolved in propylene glycol (maximum 200 ppm).

Stability /Reactivity Glyceryl Laurate is classified as a combustible material

(Lewis 1993). It is compatible with most emulsifiers, but is inactivated in the presence of sodium Iaury! sarcosine and ethoxyJated and propoxy Ia ted nonionics (e.g., Tween 80, a.k.a. Polysorbate 80) (Kabara 1984 ).

Glyceryl Cocoate is stable against oxidation and forms an emulsion with water when heated (Htils America, Inc., no date).

Glyceryl Isostearate reacts with strong acids and oxidizing agents. Additionally, incomplete combustion of Glyceryl Isostearate leads to the release of monoxyd carbon and dioxyd carbon (Gattefosse s.a. 1999).

USE

Cosmetic Use Glyceryl Monoesters are used mostly as skin conditioning

agents-emollients and/or surfactant-emulsifying agents, but several other uses are reported (Pepe, Wenninger, and McEwen 2002). The current function in cosmetics for each ingredient in this safety assessment is summarized in Table 5.

Table 6 presents information on the types of products in which these ingredients are used (FDA 1998; CTFA 1999), the frequency with which they are used as reported by industry to FDA (FDA 1998), and the current concentration at which the ingredients are used as reported by industry (CTFA 1999). Although only 16 of the 43 ingredients in this safety assessment were reported to FDA as being used in cosmetics, the current concentration of use data received from the cosmetics industry indicates that four additional glyceryl monoesters are in use. Also, concentrations of use are reported in product groups for which no uses were reported in 1998.

Cosmetic products containing glyceryl monoesters are applied to most areas of the body, and could come in contact with the ocular and nasal mucosae. These products could be used on a daily basis, and could be applied frequently over a period of several years.

None of the 43 ingredients reviewed in this safety assessment is included among the substances listed as prohibited from use in cosmetic products marketed in the European Union (European Economic Community 2001).

Japan describes the following 11 categories of cosmetic preparations: 1. skin cleansing; 2. hair care; 3. treatment;



TABLES Functions of Gl>'ceryl Monoesters in Cosmetics (Pepe, Wenninger, and McEwen 2002)

Ingredients

Glyceryl Laurate Glyceryl Laurate SE Glyceryl Laurate/Oleate Glyceryl Adipate Glyceryl Alginate Glyceryl Arachidate

Glyceryl Arachidonate Glyceryl Behenate Glyceryl Caprate Glyceryl Caprylate Glyceryl Caprylate/Caprate Glyceryl Citrate/Lactate/Linoleate/Oleate Glyceryl Cocoate Glyceryl Collagenate

Glyceryl Erucate Glyceryl Hydrogenated Rosinate Glyceryl Hydrogenated Soyate Glyceryl Hydroxystearate Glyceryl Isopalmitate Glyceryl Isostearate Glyceryl Isostearate/Myristate Glyceryl Isostearates Glyceryl Isotridecanoate/Stearate/ Adipate Glyceryl Lanolate

Glyceryl Linoleate Glyceryl Linolenate Glyceryl Montanate Glyceryl Myristate Glyceryl Oleate SE Glyceryl Oleate/Elaidate Glyceryl Palmitate Glyceryl Palmitate/Stearate Glyceryl Palmitoleate Glyceryl Pentadecanoate Glyceryl Polyacrylate Glyceryl Rosinate Glyceryl Sesquioleate Glyceryl/Sorbitol Oleate/Hydroxystearate Glyceryl Stearate/Acetate Glyceryl Stearate/Maleate Glyceryl Thiopropionate Glyceryl Undecylenate

Functions

Skin-conditioning agent-emollient and/or surfactant-emulsifying agent As above As above As above Skin-conditioning agent-emollient; viscosity-increasing agent-aqueous Skin-conditioning agent~emollient; surfactant-emulsifying agent;

viscosity-increasing agent-nonaqueous Skin-conditioning agent-emollient and/or surfactant-emulsifying agent Skin-conditioning agent-emollient and/or surfactant-emulsifying agent As above As above As above As above As above Hair-conditioning agent; skin-conditioning agent-emollient; skin-conditioni11g

agent-miscellaneous Skin-conditioning agent-emollient and/or surfactant-emulsifying agent As above As above As above As above As above As above As above As above Hair-conditioning agent; Skin-conditioning agent-emollient;

surfactant-emulsifying agent Skin-conditioning agent-emollient and/or surfactant-emulsifying agent As above As above As above Skin-conditioning agent-emollient and/or surfactant-emulsifying agent As above As above As above As above As above Film former As above As above As above As above As above Hair-waving/straightening agent; reducing agent Skin-conditioning agent-emollient; surfactant-emulsifying agent

4. makeup; 5. fragrance; 6. suntan/ sunscreen; 7. nail makeup; 8. eyeliner; 9. lip product; 10. oral product; and 11. bath product. Table 7 lists the ingredients in this safety assessment according to the International Cosmetic Ingredient

Dictionary and Handbook name (INCI name), the categories for which there is precedent (or not) for use in Japan, and any limitations on use (Rempe and Santucci 1997).



TABLE6. Product formulation data on Glyceryl Monoesters

Product category (~umber of formulations reported to FDA)

(FDA 1998)

Glyceryl Laurate Eye shadow (551) Eye makeup remover (99) Other fragrance preparations (173) Permanent waves (211) Shampoos (noncoloring) (85 J) Tonics, dressings, and other hair-grooming aids (577) Wave sets (53) Other hair preparations (noncoloring) (276) Bath soaps and detergents (405) Deodorants (underarm) (247) Douches (5) Other personal cleanliness products (307) · Skin cleansing (cold creams, c~eansing lotions, liquids, and pads) (733) Body and hand creams, lotions, powders, and sprays (excluding shaving

preparations) (827) Moisturizing skin care preparations (creams, lotions, powders, and

sprays) (881) Other skin care preparations (715)

1998 total uses for Glyceryl Laurate Glyceryl Alginate

Moisturizing skin care preparations (creams, lotions, powders, and sprays) (881)

Body and hand creams, lotions, powders, and sprays (excluding shaving preparations) (827)

1998 totals for Glyceryl Alginate Glyceryl Arachidonate

Suntan gels, creams, and liquids (136) 1998 totals for Glyceryl Arachidonate Glyceryl Behenate

Mascara (187) Suntan gels, creams, and liquids ( 131)

1998 totals for Glyceryl Behenate Glyceryl Caprylate/Caprate

Hair sprays (aerosol fixatives) (267) Body and hand creams, lotions, powders, and sprays (excluding shaving

preparations) (827) 1998 totals for Glyceryl Caprylate/Caprate Glyceryl Cocoate

Bubble bath (209) Lipstick (942) Bath soaps and detergents ( 405) Cleansing skin care preparations (creams, lotions, powders, and sprays)

(733) 1998 totals for Glyceryl Cocoate Glyceryl Erucate ·

Face and neck creams, lotions, powders, and sprays (excluding shaving preparations) (304)

1998 totals for Glyceryl Erucate

Number of formulations containing ingredient

(FDA 1998)

2

1 ' 9

4 4

3

5

29

2 2

Current concentration of

use (CTFA 1999) (%)

0.1

0.3-2 0.4 0.4 0.4

0.3

4

4

0.5

2 5

2

1 0.3-2 4 1-5

0.5


GL YCER YL MONOESTERS

TABLE6 ,,

Product formulation data on Glyceryl Monoesters (Continued)

Product category (number of formulations reported to FDA)

(FDA 1998)

Glyceryl Hydroxystearate Other eye makeup preparations (151) Lipstick (942) Deodorants (247) Other personal cleanliness products (307) Shaving Cream (133) Cleansing skin care preparations (creams, lotions, powders, and sprays)

(733) Face and neck creams, lotions, powders, and sprays (excluding shaving

preparations) (304) Body and hand creams, lotions, powders, and sprays (excluding shaving

preparations) (827) Foot powders and sprays (35) Moisturizing skin care preparations ,(creams, lotions, powders,

and sprays) (881) Night skin care preparations (creams, lotions, powders, and sprays) (200) Paste masks (mud packs) (269) Other skin care preparations (creams, lotions, powders, and sprays) (715) Suntan gels, creams, and liquids (131)

1998 totals for Glyceryl Hydroxystearate Glyceryl lsostearate

Bath oils, tablets, and salts (140) Eye shadow (551) Eye lotion (23) Face powders (301) Foundations (319) Skin cleansing (cold creams, cleansing lotions, liquids, and pads) (733) Face and neck creams, lotions, powders, and sprays (excluding shaving



sprays) (881) Night skin care preparations (creams, lotions, powders, and sprays) (200) Paste masks (mud packs) (269) Other skin care preparations (creams, lotions, powders, and sprays) (715)

1998 totals for Glyceryl Isostearate Glyceryl Lanolate

Body and hand creams, lotions, powders, and sprays (excluding shaving preparations) (827)

Moisturizing skin care preparations (creams, lotions, powders, and sprays) (881)

1998 totals for Glyceryl Lanolate Glyceryl Linoleate

Eye shadow (551) Other fragrance preparations ( 173) Face powders (301)


(FDA 1998)

4

5

2

1 8

1 4 3 1

32

23

1 24

2

32

2

3

69

Cunent concentration of

use (CTFA 1999) (%)

2

2

2

0.8

0.5-2 0.8

4-6 3 2

2

3

0.3




TABLE6 Product formulation data on Glyceryl Monoesters (Continued)


(FDA 1998)

Foundations (319) Lipstick (942) Other personal cleanliness products (307) Cleansing skin care preparations (creams, lotions, powders, and sprays)




sprays) (881) Paste masks (mud packs) (269) Other skin care preparations (creams, lotions, powders, and sprays) (715)

1998 totals for Glyceryl Lin oleate Glyceryl Linolenate

Eye shadow (551) Foundations (319) Lipstick (942) Other personal cleanliness products (307) Cleansing skin care preparations (creams, lotions, powders, and sprays)




sprays) (881) Other skin care preparations (creams, lotions, powders, and sprays) (715)

1998 totals for Glyceryl Linolenate Glyceryl Myristate

Other fragrance preparations (173) Makeup bases ( 136) Deodorants (underarm) (247) Face and neck creams, lotions, powders, and sprays (excluding shaving



sprays) (881) Night skin care preparations (creams, lotions, powders, and sprays) (200) Paste masks (mud packs) (269) Other skin care preparations (creams, lotions, powders, and sprays) (715) Suntan gels, creams, and liquids (131) Other suntan preparations (37)

1998 totals for Glyceryl Myristate Glyceryl Oleate/Elaidate

Foundations (319) Makeup bases (136)


(FDA 1998)

2 3

3

2

2

17

3

2

2

10

1 3

2

4

1 3

1 19

Current concentration of

use (CTFA 1999) (%)

0.7 0.7 0.7

0.7 0.7 0.7

1-6

6

6

2 0.3



TABLE6 Product formulation data on Glyceryl Monoesters (Continued)


(FDA 1998)

Number of formulations containing ingredient ·

(FDA 1998)

Current concentnition of

use (CTFA 1999) (%)


2

Moisturizing creams, lotions, powders, and sprays (881) 1998 totals for Glyceryl Oleate/Elaidate Glyceryl Polyacrylate

Hair conditioners (630) Tonics, dressings, and other hair-grooming aids (577)

2


0.4 0.2 2

1998 totals for Glyceryl Polyacrylate Glyceryl Rosinate

Eyebrow pencil (99) Eye shadow (551) Mascara ( 187) Other hair coloring preparations (59) Blushers (all types) (243) Foundations (319) Lipstick (942) Depilatories (28)

1998 totals for Glyceryl Rosinate Glyceryl Stearate/Acetate

Tonics, dressings, and other hair-grooming aids (577)

10 2

2 0.08-12 3 2 0.06-4 0.4-6

1 4

7 Skin cleansing (cold creams, cleansing lotions, liquids, and pads) (733) Face and neck creams, lotions, powders, and sprays (excluding shaving

1 2

preparations) (304) Body and hand creams, lotions, powders, and sprays (excluding shaving 2

preparations) (827) Moisturizing creams, lotions, powders, and sprays (881) Suntan gels, creams, and liquids (131) Indoor tanning preparations (68)

1998 totals for Glyceryl Stearate/Acetate Glyceryl Undecylenate

Moisturizing creams, lotions, powders, and sprays (881) 1998 totals for Glyceryl Undecylenate

Noncosmetic Use Glyceryl Laurate has noncosmetic uses as an emulsifying and

dispersing agent for food products, oils, waxes, and solvents; an antifoaming agent; and a dry-cleaning soap base (Lewis 1993). It has also been detected in pharmaceutical excipients (Giron, Link, and Bouissel 1992).

Glyceryl Caprylate has been used to dissolve gallstones by direct biliary infusion (Budavari 1989).

Glyceryl Isostearate is used in textiles (Unichema International1997b).

Glyceryl Behenate has been approved for use as a direct food additive (21 CFR 184.1328). Additionally, Glyceryl Mo-

3 3 2

2 2

noesters have been approved for use as components of adhesives, coatings, paper and paperboard, and other materials that come in contact with food (i.e., indirect food additive uses) (21 CFR 175.105; 175.300; 176.170; 176.180; 176.200; 176.210; 177.1210; 177.2800; 178.3120; 178.3800; and 178.3870).

Glyceryl Rosinate and Glyceryl Hydrogenated Rosinate both contain rosin. Rosin is regulated for use as a diluent in color additive ink mixtures for marking gum, confectionery, fruits, vegetables, and tablet forms of food supplements. Rosin (as colophony, a.k.a. Portuguese gum rosin) is listed for use as a flavoring agent in alcoholic beverages. Derivatized and some of the modified rosins are regulated as softeners for chewing gum



TABLE7 ,Glyceryl Monoesters used in Japan'(Rempe and Santucci 1997)

Category Category with no INCI name Japanese name with precedent for use* precedent for use*

Glyceryl Laurate Glyceryl Monoaurate 1, 2, 3, 4, 5, 6, 7, 9, 10, 11 8 Glyceryl Behenate Glyceryl Behenate 1, 2, 3, 4, 5, 6, 7 8, 9, 10, ,11 Glyceryl Cocoate Glycery1 Cocoate 1, 2, 3, 4, 5, 6, 7, 9, 10, 11 8 Glyceryl Erucate Glyceryl Monoerucate All Glyceryl Hydroxystearate Glyceryl Hydroxystearate (1) 1,2,3,4,5,6;7 8, 9, 10, 11

Glyceryl Hydroxystearate (2) 1, 2, 3, 4, 5, 6, 7 8, 9, 10, 11 Glyceryl Monohydroxystearate All

Glyceryl Isostearate Glyceryl Isostearate (1) 1, 2, 3, 4, 5, 6, 7, 9, 10, 11 8 Glyceryl Isostearate/Myristate Glyceryl Monoisostearate Monomyristate 1, 2, 3, 4, 5, 6, 7, 9, 10, 11 8 Glyceryl Lanolate Glyceryl Monolanolate 1,2,3,4,5,6, 7 8, 9, 10, 11 Glyceryl Linoleate Glyceryl Linoleate 1, 2, 3, 4, 5, 6, 7, 9, 10, 11 8 Glyceryl Myristate Glyceryl Monomyristate 1' 2, 3, 4, 5, 6, 7 8, 9, 10,11 Glyceryl Sesquioleate Glyceryl Sesquioleate 1, 2, 3, 4, 5, 6, 7, 9, 10, 11 8 Glyceryl Stearate/ Acetate Glyceryl Monostearate Monoacetate 1' 2, 3, 4, 5, 6, 7' 11 8, 9, 10. Glyceryl Stearate/Maleate Glyceryl Stearate Maleate

*See text for explanation of categories.

base. Wood rosin and certain derivatized modified forms of rosin are listed for use as coatings on fresh citrus fruits. Indirect uses of derivatized rosin as components of paper and paperboard in contact with dry food are permitted (FDA 1988).

BIOlOGICAl PROPERTIES

Absorption and Metabolism The metabolic fate ofmonoglycerides (glyceryl monoesters)

is summarized below. Because monoglycerides are products of triglyceride and diglyceride metabolism, these compounds are also mentioned.

Triglyceride digestion begins in the intestinal tract. Initially, the triglyceride is hydrolyzed to a,,B-diglyceride, which is then hydrolyzed to ,8-monoglyceride. These hydrolytic reactions occur at an oil-water interface. Approximately 28% of the ,8-monoglyceride is isomerized to a-monoglyceride, and approximately 75% of the a-monoglyceride is further hydrolyzed to free glycerol. Free glycerol enters the intestinal wall independent of the lipids, and it has no further use in terms of lipid absorption. The free fatty acids and glycerol are available for the resynthesis of triglycerides. ,8-Monoglycerides are not hydrolyzed because of their transfer to a water-soluble phase and, also, because of enzyme specificity. However, they can be acylated directly to triglyceride (Mattson and Volpenhein 1964).

Skin Penetration Enhancement Glyceryl Laurate

The effect of Gfycery I La urate or Dilaurate on the penetration of naloxone-HCJ across cadaver skin was evaluated using Franz diffusion cells. Naloxone is a potent opioid antagonist used for

1, 2, 3, 4, 5, 6, 7 8, 9, 10, 11

the reversal of narcosis. Naloxone concentrations in the reservoir were determined by HPLC using UV detection. Glyceryl La urate was evaluated at a concentration of I 0% in propylene glycol. The average flux through human cadaver skin (10 experiments) for naloxone alone was 1.6 ± 0.4 f.Lg/cm2 ·h. In the presence of Glyceryl Dilaurate (1 0% in propylene glycol), average Naloxone flux increased to 18.7 ± 1.8 f.Lg/cm2 ·h (3 experiments), and increased even greater in the presence of Glyceryl Laurate (23.4 ± 3.6 f.Lg/cm2·h; 3 experiments). In the presence of urea (10% in propylene glycol), the average Naloxone flux was 0.4 ± 0.1 f.Lg/cm2·h (3 experiments) (Aungst, Rogers, and Shefter I 986).

In another study, the effect of Glyceryl Laurate on penetration of the water-soluble drug, papaverine HCI through hairless rat skin (from abdominal area) was demonstrated using diffusion cells. The mean flux of papaverine HCI was 23.7 ± 5.2 f.Lg/cm2/h (three to five experiments) in the presence of 10% Glyceryl Laurate. This value was compared with the mean value for papaverine HCI flux in the presence of the water control (1.1 ± 0.2 f.Lg/cm2/h) (Okumura eta!. 1990).

Platelet Aggregation Glyceryl Arachidonate

Phosphatidylcholine liposomes containing 1-ArachidonylMonoglyceride caused aggregation of human platelets in vitro (Gerrard and Graff 1980).

Enzyme Activity Glyceryl Laurate

The effect of Glyceryl Laurate and various fatty acids and derivatives on Sa-reductase activity in vitro was evaluated


GLYCERYL MONOESTERS 73

because of the established link between cancer of the prostate gland and high dietary fat intake. Prostate gland tissue specimens (human) were used. Sa-Reductase catalyzes the reduction of testosterone to dihydrotestosterone, which controls cellular division in the prostate gland. It has been suggested that the modulation/inhibition of this enzyme could prevent carcinogenesis in the prostate gland. Results indicated that the inhibitory effect of lauric acid on Sa-reductase activity was decreased by esterification to Glyceryl La urate and was totally lost by esterification to Glyceryl Dilaurate and Trilaurin (Niederprucm et al. 199S).

Signal Transduction This section is included because glyceryl diesters may be

present in glyceryl monoester ingredients. Although most glyceryl diesters that are found would be expected to be 1,3-glyceryl diesters, some may be 1 ,2-diesters, which can have signal transduction effects.

Lee and Severson (1994), in a review signal transduction in smooth muscle, state that the generation of intracellular second messengers is a common mechanism of signal transduction for external stimuli such as hormones, neurotransmitters, growth factors, and drugs (agonists) that interact with plasma membrane receptors. They go on to say that the established role of phospholipid turnover in signal transduction mechanisms is based on the observations that agonist-induced hydrolysis of a minor phospholipid in the plasma membrane, phosphatidylinositol 4,S-bisphosphate (PIPz), in a reaction catalyzed by a phosphoinositide-specific phospholipase C (Pl-PLC) enzyme generated the following two intracellular second messengers: (1) inositol 1 ,4,S-triphosphate (IP3), responsible for the mobilization of Ca2+ from intracellular stores, and (2) diacylglycerol, responsible for the activation of protein kinase C (PKC). Levy et al. (1994) reported that PKC consists of a family of 10 isozymes that phosphorylate serine and threonine residues. Classical PKC isozymes (a, f3~o fJn, y) are dependent on Ca2+ and phospholipids and are activated by diacylglycerol. These isozymes transduce mitotic signals induced by growth factors.

Sanchez-Piiiera et al. (1999) studied the lipid activation of PKC a by comparing the activation capacity of different 1,2-diacylglycerols and 1 ,3-diacylglycerols incorporated into mixed micelles or vesicles. PKC a, as well as other isoenzymes in this family, are activated by Ca2+, phosphatidylserine, and diacylglycerols. Diacylglycerols are considered to be hydrophobic anchors that may recruit PKC to the membrane, leading to an increase in the enzyme's membrane affinity and to the activation ofPKC.

Unsaturated 1 ,2-diacylglycerols were more potent activators of protein kinase C a than saturated 1 ,2-diacylglycerols when 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine (POPS)/Triton X-1 00 mixed micelles and pure POPS vesicles were used. These differences were not observed when 1-palmitoyl -2-oleoyl-snglycero-3-phosphocholine (POPC)/POPS ( 4:1 molar ratio) vesicles were used. Additionally, 1,2-diacylglycerols had a consid-

erably greater activating capacity than 1 ,3-diacylglycerols in POPS Triton X- 100 mixed micelles and in PO PC/POPS vesicles. However, the difference between 1,2- and 1 ,3-diacylglycerols was smaller when pure POPS vesicles were used. Th,at is, both were able to activate PKC a practically to the same extent. Nevertheless, saturated diacylglycerols induced significant activation of PKC a in Triton X- 100 micelles and in pure POPS vesicles in this study (Sanchez-Piiiera et al. 1 999).

Unlike the preceding study, a very low capacity for 1,3-diacylglycerol-induced activation was demonstrated in an earlier study (Nomura et al. 1 986). In the Nomura et al. (1986) study, however, sonicated phosphatidylserine vesicles were used, whereas unsonicated preparations of multi lamellar vesicles were used in the Sanchez-Piiiera et al. (1999) study.

Cell Growth and Proliferation

This section is included because glyceryl diesters may be present in glycerylmonoester ingredients. Although most glyceryl diesters that are found would be expected to be 1 ,3-glyceryl diesters, some may be 1 ,2-diesters, which can have cell growth and proliferation effects.

Huckle and Earp (1994) report that activation of the type 1 angiotensin II receptor rapidly increases intracellular levels of inositol phosphates, notably inositol I ,4,5-triphosphate (IP3), and 1 ,2-diacylglycerol (DAG) in adrenal cortical cells, hepatocytes, and vascular smooth muscle. The type 1 angiotensin II receptor is responsible for all known physiologic actions of angiotensin II. Angiotensin II, an octapeptide, is well known as an acute regulator of vasomotor tone and fluid homeostasis. It exhibits many characteristics of the 'classical' peptide growth factors such as epidermal growth factor/transforming growth factor alpha (EGF/TGFa), platelet-derived growth factor (PDGF), and insulin-like growth factor (IGF)-1. Characteristics of these growth factors include the regulation of growth in a selfcontained autocrine/paracrine fashion, and the ability to stimulate tyrosine phosphorylation, to activate MAPKs (mitogenactivated protein kinases ), and to increase expression of nuclear proto-oncogenes. Angiotensin II has trophic or mitogenic (increases rate of cell division) effects on a variety of target tissues, including adrenal cells and vascular smooth muscle cells.

In vascular smooth muscle, hydrolysis via the lipase pathway is the predominant metabolic fate of diacylglycerol. The activation ofPKC in vascular smooth muscle modulates agoniststimulated phospholipid turnover, produces an increase in contractile force, and regulates cell growth and proliferation (Lee and Severson 1994).

Blobe, Obeid, and Hannun (1994) reviewed various studies indicating that the sustained activation or inhibition of PKC (diacylglycerol-activated isoenzyme) activity in vivo may play a critical role in the regulation of long term cellular events such as proliferation, differentiation, and tumorigenesis. Many of the signals transduced by PKC are mitogenic signals that have been sent by growth factors (e.g., platelet-derived growth factor [PGDF] and epidermal growth factor [EGF]). For



example, PGDF binds to its high-?ffinity receptor (PDGFR) and activates this receptor's intrinsic tyrosine kinase activity to mediate the initiation of DNA synthesis and other cellular effects. It is important to note that PKC has been linked directly to the pathogenesis of human skin, colon, and breast cancers. In the epithelium, long-term changes in PKC activity, either through the action of phorbol esters or by specific changes in PKC isoenzyme levels, either leads to growth of melanocytes, the differentiation of keratinocytes, or to transformation. In colon cancer, PKC acts as a tumor suppressor. Thus, decreasing the levels of PKC activity can result in transformation. In breast cancer, an increase in PKC activity appears to correlate with enhanced oncogenicity.

Evidence of increased PKC activity in hyperplastic pituitary cells has also been reported. Furthermore, the increase in diacyl- . glycerol content paralleled the increase in PKC activity (Levy etal.1994).

Antimicrobial Activity

Glyceryl Laurate . Lauricidin (registered trademark for Glyceryl Laurate) has

been described as having a wide spectrum of antimicrobial activity against diverse microbial species (viruses, fungi, molds, yeasts, and bacteria included). However, it is generally inactive against gram-negative bacteria. When Lauricidin was tested in cell culture using 16 human RNA- and DNA-enveloped viruses, all viruses were reduced in infectivity by 99.9% at relatively low concentrations (1.0%) of Lauricidin. Antifungal activity (inhibition of mycelial growth) of Glyceryl LaUJ·ate has been demonstrated in 12 strains at a concentration of 0.5%, and in three additional strains at a concentration of 0.05% (Kabara 1984 ).

Glyceryl Laurate inhibited the production of staphylococcal toxic shock toxin-1, the toxin responsible for toxic shock syndrome, at assay concentrations of 20, 100, and 300 {lglml (Schlievert et al. 1992) and 17 mg!L (Holland, Taylor, and Farrell 1994). Projan et al. (1994) reported that Glyceryl Laurate inhibited the synthesis of most staphylococcal toxins at the level of transcription. It blocked the induction but not the constitutive synthesis of ,8-lactamase, suggesting that transmembrane signal transduction was the target of Glyceryl La urate action.

Other studies on the bactericidal activity of Glyceryl Laurate include inhibition of bacterial spores and vegetative cells (Chaibi, Ababouch, and Busta 1996a, 1996b); inhibition of Listeria monocytogenes (Oh and Marshall 1996); and susceptibility of Heliobactor pylori (Petschow, Batema, and Ford 1996).

ANIMAL TOXICOLOGY

General The safety of mono- and diglycerides in food has been re

viewed by the Fciod Protection Committee of the National Academy of Sciences National Research Council Food and Nutrition Board (National Academy of Sciences 1960). The Food

Protection Committee concluded that there appears to be no re·ason to question the safety of mono-, di-, or triglycerides of lauric acid (i.e., Glyceryl Lam·ate, Glyceryl Dilaurate, or Glyceryl Trilaurate [Trilaurin]) as food additives. This conclusion was based on the following: (1) Lauric acid glycerides are used in important foods, such as human and cow's milk, at concentrations of 3% to 6% and large quantities are present in coconut oil. The use of these foods has not been accompanied b'y recognized toxic effects. (2) Lauric acid glycerides undergo the usual metabolic changes of the higher fatty acids. (3) When lauric acid glycerides are fed in diets containing a variety of glycerides, there is not evidence of a specific toxic or harmful effect.

Acute Inhalation Toxicity Glyceryl Law·ate

A low-grade irritant response was noted following inhalation of an aerosol containing 1 0% Glyceryl La urate. The strain of animals tested and details concerning the test protocol and study results were not included (Unichema International 1997b ).

Acute Oral Toxicity Glyceryl Laurate

The acute oral toxicity of Glyceryl Lam·ate was evaluated using 31 male rats (strain not stated; weights = 150 to 220 g). The test substance was administered by stomach tube after 18 h offasting. An LDso of53.4ml/kg was reported (Eagle and Poling 1955).

Glyceryl Laurate (in olive oil) was administered orally to young Wistar rats (weights not stated). Doses of 10,000 and 20,000 mg/kg were administered to five male and five female rats, respectively. The LD50 was > 20,000 mg/kg. (Henkel KgaA 1994).

Glyceryllsostearate

A single oral dose (2 g/kg body weight) of Glyceryl Isostearate did not result in any harmful effects in rats. Details concerning the test protocol were not provided (Unichema Intemational 1997a).

Glyceryl Rosinate

The acute oral toxicity of undiluted, Purified Ester Gum-2-0ctyldodecyl Myristate (contains 50% Glyceryl Rosinate and 50% octyldodecyl myristate) was evaluated using fasted Wistar albino rats (five males, five females; weight range 220 to 292 g). A single oral dose of the test substance (5 g/kg) was administered to each animal. Dosing was followed by a 14-day observation period, and gross necropsy (results not included) was performed on all animals. None of the animals died, and it was concluded that the test substance was not toxic (LD5o > 5 g/kg) (Consumer Product Testing Company 1990a).



Glyceryl Citrate/Lactate/Linoleate!Oleate Hiils AG ( 1996a) provided unpublished data on the acute oral

toxicity of Glyoeryl Citrate/Lactate/Linoleate/Oleate using five male and five female Wistar rats. The undiluted test substance (highly viscous) was liquefied by heating in a water bath and then administered to each animal using a rigid gastric pharyngeal probe. Each rat received a single oral dose of 2000 mg/kg (dose volume= 2.004 mllkg body weight). The animals were observed over a period of 14 days after dosing. None of the animals died. Body weight gain was described as normal, and no signs of toxicity were noted. Grossly detectable organ changes were not noted at necropsy. The LD5o was > 2000 mg/kg in male and female rats.

Acute Dermal Toxicity Glyceryi Citrate!Lactate/Linoleate!Oleate

The acute dermal toxicity of Glyceryl Citrate/Lactate/ Linoleate/Oleate was evaluated using five male and five female Wistar rats. The undiluted test substance (highly viscous) was liquefied by heating in a water bath and then applied dermally (dose= 2000 mg/kg; dose volume= 2.004 ml/kg) to each animal using a gauze patch. Each patch was secured with a semi occlusive dressing for 24 h. None of the animals died, and gross lesions were not observed. Particularly, no gross changes were observed in the subcutaneous tissue in the area of application. The acute dermal LD50 was >2000 mg/kg in male and female rats (Hi.ils AG 1996b).

Short-Term Inhalation Toxicity

Glyceryl Laurate The short-term inhalation toxicity of Glyceryl Laurate was

evaluated using rats. The animals were given a total of 14 1-hour exposures during a 3-week period. Although details concerning the test protocol and study results were not included, a no-effect level of 280 mg/m3 was reported (Unichcma International 1997b ).

Short-Term Oral Toxicity

Glyceryl Law·ate The short-term oral toxicity of Glyceryl Lam·ate was evalu

ated using 10 weanling rats. The test substance was administered orally at a concentration of 25% in the diet for a period of 10 weeks. No gross or microscopic lesions were found that were attributable to administration of the test diet (Procter & Gamble Company 1950).

Chronic Oral Toxicity

Glyceryl Laurate Fitzhugh, Schouboe, and Nelson (1960) fed two groups of24

albino rats of the Osborne-Mendel strain a mixture consisting of Trilaurin (8%), Glyceryl Dilaurate (45%), and Glyceryl Lam·ate ( 40% to 45%) at a concentration of 25% in the diet for 2 years.

The individual glyceryl esters were fed at effective dietary concentrations of ~2% (Trilaurin), ~ 11% (Glyceryl Dilaurate), and~ 10% to II% (Glyceryl Laurate). Of the two control groups, one was fed 25% hydrogenated cottonseed oil in the,diet (concurrent control), and, the other, basal diet only.

After 26 or 52 weeks of dosing, no significant differences in weight gain between the test and concurrent control groups were noted. No significant differences in the total number of deaths were noted when the test group was compared with both control groups. At necropsy, no gross lesions were observed in test animals. At microscopic examination, a slight increase in hepatic cell fatty change was observed in test animals, compared to the control group fed the basal diet. However, this finding in test animals was no greater than that observed in the control group fed hydrogenated cottonseed oil. The same difference occurred to a lesser and questionably significant degree when the incidence of intrahepatic bile duct proliferation in test animals was compared to that noted in controls (Fitzhugh, Schouboe, and Nelson 1960).

Ocular Irritation

Glyceryl La urate The ocular irritation potential of undiluted Glyceryl Laurate

was evaluated in the Draize test using three albino rabbits. The test substance (0.1 ml) was instilled into the conjunctival sac of one eye of each animal. Untreated eyes served as controls. Ocular reactions were scored every 24 h up to day 7 post instillation. Mean scores (average of 24-, 48-, and 72-h readings) for corneal reactions and erythema of the conjunctiva were 0.17 (maximum score, corneal lesions= 80) and 1.33 (maximum score, conjunctival lesions= 20), respectively. Reactions were not observed in the iris (Henkel KgaA 1994).

Kabara (1984) evaluated the ocular irritation potential of a 20% Glyceryl Laurate emulsion using six albino rabbits. The test substance (0.1 ml) was instiJled into the conjunctival sac of the right eye of each animal. Untreated left eyes served as controls. Ocular reactions were scored at 24, 48, and 72 h post instillation according to the Draize scale: 0 to 110.

According to the test protocol, reactions would be classified as positive if the test substance induced any of the following: ulceration of the cornea (other than a slight dulling of the normal luster), inflammation of the iris (other than a slight circumcorneal injection of the blood vessels), or if the substance produced in the conjunctivae an obvious swelling with partial eversion of the lids or a diffuse crimson-red with individual vessels not easily discernible. Study results were positive only if four or more animals had positive reactions.

An average irritation score (six animals) ofO was reported for both corneal opacity and inflammation of the iris. The average irritation score for conjunctival irritation was 3.7. Because only one rabbit had a positive reaction, the 20% Glyceryl Laurate emulsion was classified as a "negative ocular irritant" (Kabara 1984).



Glyceryl Jsostearate Although details concerning the test protocol were not pro

vided, Unichema International (1997a) concluded that Glyceryl Isostearate was not an ocular irritant in rabbits. Reactions classified as minior ocular initation had cleared by 48 h post instillation, reactions were not observed in the cornea or iris.

In a study by the Institut Franyais de Recherches et Essais Biologiques (1977), the ocular irritation potential of Glyceryl Isostearate was evaluated using six male New Zealand white rabbits. The test substance (undiluted, 0.1 ml) was instilled into the left conjunctival sac of each animal. Untreated right eyes served as controls. After instillation, the eyelids were held together for several seconds to avoid loss of the test substance. The animals were restrained for a period of 18 h. Ocular reactions were scored at 1, 2, 3, 4, and 7 days post instillation (maximum score= 20). Glyceryl Jsostearate was classified as a nonirritant.

The Centre de Recherche et d'Elevage des Oncins (1975) evaluated a mixture consisting of Glyceryl Jsostearate in an ocular irritation test. Other components of the mixture included glyceryl stearate, propylene glycol isostearate, propylene glycol stearate, ceteth-25, and oleth-25, but the concentration of each component was not provided. The mixture, 20% in sterile water, was instiJled (0.1 ml) into the conjunctival sac of the left eye of each of six New Zealand rabbits. Contralateral eyes served as controls. Reactions were scored at 24, 48, and 72 h post instillation according to the Draize scale. Mean Draize ocular irriation scores were 3.0 (at 24 h), 2.67 (at 48 h), and 1.67 (at 72 h). Total Draize scores (Scale: 0 to 11 0) were 18, 16, and 10 at 24 h, 48 h, and 72 h, respectively. The mixture was classified as a nonirritant based on the mean ocular irritation scores that were recorded.

Glyceryl Rosinate The ocular irritation potential of undiluted, Purified Ester

Gum-2-0ctyldodecyl Myristate (contains 50% Glyceryl Rosinate and 50% octyldodecyl myristate) was evaluated using six New Zealand white rabbits. The test substance was instilled (0.1 ml) into the conjunctival sac of one eye of each animal. Untreated eyes served as controls. Eyes were not rinsed for up to 24 h post instiJlation. Ocular reactions were scored at 24, 48, and 72 h post instiJlation according to the Draize scale (maximum total score= 11 0). Reactions were also scored at days 4 and 7 if irritation reactions persisted. Average Draize scores of 1.3 and 0.3 were reported at 24 and 48 h post instillation, respectively. At 72 h, an average score of 0 was reported. The test substance was not an ocular irritant (Consumer Product Testing Company

1990b).

Glyceryl Citrate/Lactate!Linoleate/Oleate The ocular irritation potential of Glyceryl Citrate/Lactate/

Linoleate/Oieate was evaluated using three female rabbits. The test substance (0.1 ml) was instilled into the conjunctival sac of one eye of each animal. At 24 h post instillation, the eyes were flushed with warm physiological saline solution. The conjunctivae, iris, and cornea were examined for any signs of ocular

irritation at 24, 48, and 72 h post instillation. Ocular initation was not observed in either of the three rabbits tested (Htils AG 1996c).

Skin Irritation Glyceryl Law·ate

Kabara ( 1984) eva! uated the skin irritation potential of a 20% Glyceryl Laurate emulsion using six albino rabbits. The test substance, 0.5 ml, was applied to both an abraded and intact skin site (clipped free of hair) on each animal, and each site was then covered with an occlusive patch. Patches were secured with adhesive tape, and the entire trunk of each animal was wrapped with an impervious material. The animals were immobilized during the 24-h contact period.

At 24 hand 72 h after patch removal, reactions at abraded and intact sites were scored according to the following scales: 0 (no erythema) to 4 (severe erythema to slight eschar formations); and 0 (no edema) to 4 (severe edema).

The primary irritation score for the group of six rabbits was 3.9, classifying the Glyceryl Laurate emulsion as a moderate skin irritant (Kabara 1984).

Henkel KgaA ( 1994) reported the results of a study to evaluate the skin irritation potential of undiluted Glyceryl Laurate using six rabbits. The test substance was applied (0.5 g under an occlusive patch) to dorsal skin of each animal. The test sites of three rabbits were shaved and those of the remaining three were scarified. Reactions were scored after 24 h and 72 h. Glyceryl Lam·ate induced minor erythema (mean score= 0.8) and edema (mean score = 0.9) in animals with intact skin. The scores for the three rabbits with scarified skin were not included.

Although details concerning the test protocol and study results were not included Unichema International (1997b) reported that Glyceryl Laurate was less irritating to the skin of rabbits, on an active for active basis, than sodium Iaury! sulfate (SLS). Solutions of Glyceryl Lam·ate were equivalent in irritancy to SLS concentrations of approximately one fifth the strength.

Glyceryl Jsostearate Biogir S.A. Conseil Recherche (1989) conducted a study in

which the skin irritation potential of Glyceryl Isostearate was evaluated using three New Zealand albino rabbits. The test substance (0.5 ml on hydrophilic gauze) was applied to skin, clipped free of hair, on the right side of each animal. Patches were secured with hypoaJlergenic microporous adhesive tape and then covered with elastic material that sunounded the animal's torso. After 4 h of contact, all patches were removed. A gauze square moistened with 0.5 ml of distilled water was applied to a control site on the left side of each animal according to the same procedure.

At 1, 24, 48, and 72 h post removal of the semi occlusive bandage, reactions were scored according to the following scales: 0 (no erythema) to 4 (severe erythema, with or without formation of scars and presence of a lesion representing a significant reaction such as a burn or necrosis); 0 (no edema) to 4 (severe



edema). Because slight irritation persisted beyond 72 h post removal, the animals were observed until all lesions had regressed completely.

Mild erythema was observed in two rabbits at I, 24, and 48 h post removal. A more severe reaction (moderate irritation) was observed in the third rabbit; the reaction did not clear until day 5. Very mild edema was noted in two rabbits at I h post removal, and persisted to 48 h post removal in one rabbit. Slowly reversible, slight changes in the structure of the skin were also observed. It was concluded that Glyceryl Isostearate was not a skin irritant in albino rabbits (Biogir S.A. Conseil Recherche 1989).

The Institut Fran~ais de Recherches et Essais Biologiques (1977) evaluated the skin irritation potential of Glyceryl Isostearate using six male New Zealand albino white rabbits. A sterile absorbent gauze pad containing the test substance (0.5 ml) was applied to a scarified site on the right flank and an intact site on the left flank of each animal. Both sites had been clipped free of hair. Each gauze pad was secured with a non-allergenic, adhesive occlusive patch.

The patches remained in place for 23 h; reactions were scored at 24 and 72 h post application according to the following scales: 0 (no erythema) to 4 (severe erythema, crimson red, with slight eschar formation [injuries in depth]) and 0 (no edema) to 4 (severe edema, raised more than 1 mm and extending beyond area of application). The primary irritation index (PII) was calculated after all scores had been recorded. Glyceryl Isostearate was classified as a non irritant (PII = 0.21) (lnstitut Fran~ais de Recherches et Essais Biologiques [IFREB] 1977).

The Centre de Recherche et d'Elevage des Oncins (1975) evaluated a mixture consisting of Glyceryl Isostearate and glyceryl stearate, propylene glycol isostearate, propylene glycol stearate, ceteth-25, and oleth-25 in a skin irritation test using rabbits. The concentrations of each component were not stated. The mixture (0.5 ml, 20% in sterile water) was applied to an intact site and an abraded site (each 2 cm2 and clipped free of hair) on each of six male New Zealand rabbits. A non allergenic, adhesive patch was placed over each test site, and the trunk of each animal was wrapped with an adhesive plaster. Patches were removed at 24 h post application and reactions scored (at 24 h and 72 h) according to the scales indicated in the preceding paragraph. The mixture was classified as a slight irritant (PII = 0.92).

Glyceryl Rosinate The skin irritation potential of undiluted, Purified Ester Gum-

2-0ctyldodecyl Myristate (contains 50% Glyceryl Rosinate and 50% octyldodecyl myristate) was evaluated using six New Zealand white rabbits. The test substance (0.5 ml) was applied to abraded and intact skin (two sites per animal), and sites were covered with occlusive patches for 24 h. The patches were secured with hypoallergenic cloth tape and the entire trunk of each animal was encased in an impermeable plastic, occlusive wrapping. Reactions were scored at 24 and 72 h post application according to the following scales: 0 (very slight erythema, barely

perceptible) to 4 (severe erythema [beet redness] to slight eschar formation [injuries in depth]) and 1 (very slight edema, barely perceptible) to 4 (severe edema, area raised approximately 1 mm and extending beyond area of exposure). The mean scrores at 24 and 72 h were averaged and a PII calculated. A PII of 3.40 (potential for severe irritation-warning label may be considered) was reported (Consumer Product Testing Company 1990c).

Glyceryl Citrate!Lactate/Linoleate/Oleate

In an acute dermal toxicity study summarized earlier in the report text, undiluted Glyceryl Citrate/Lactate/Linoleate/Oleate (heated) was applied to the skin ofWistar rats (five males, five females). The test substance (dose= 2000 mg/kg; dose volume= 2.004 mllkg) was applied to each animal using a gauze patch, and each patch was secured with a semiocclusive dressing for 24 h. Neither erythema nor edema was observed in any of the animals tested (H Uls AG 1996b ).

HU!s AG ( 1996d) reported another study of the skin irritation potential of undiluted Glyceryl Citrate/Lactate/Linoleate/Oleate using three rabbits (strain not stated). The test substance was applied to shaved, intact skin for 4 h. At 24 h post application, clearly circumscribed erythema and very mild to clear edema were observed. Barely perceptible to clearly circumscribed erythema and very mild edema were observed at 48 and 72 h post application. After day 6 post application, erythema and swelling were barely detectable. In one animal, a brown stain was noted at the application site; the skin surface was described as dry and squamous. Very slight erythema, dryness, and scaling were noted in all animals on day 8. These reactions were accompanied by slight swelling in one of the three animals. All reactions classified as erythema or edema had cleared by day I 0 post application. Scaling was observed in one animal (day 1 0), but had cleared by day 14. The average score for erythema and scabbing (24, 48, and 72 h readings included) was 1.67. The average score for edema formation (24-, 48-, and 72-h readings included) was 1.11.

Comedogenicity The comedogenicity of undiluted, Purified Ester Gum-2-

0ctyldodecyl Myristate (contains 50% Glyceryl Rosinate and 50% octyldodecyl myristate) was evaluated using three male New Zealand white rabbits (3 months old). The test substance (0.1 ml) was applied to the internal base of the right ear of each rabbit 5 days per week for 3 weeks (15 applications per rabbit). Untreated left ears (internal base) served as controls. Test sites were evaluated for comedone formation and enlarged pores daily. Terminal biopsies of treated and control ears were performed. All specimens were graded for the extent of acanthosis, keratosis, and keratin ("plugging") according to the following scale: 0 (no different from untreated/treated control) to 3 (approximately 75% greater than untreated/treated control). At gross examination, erythema at the application site was noted in all three rabbits. At microscopic examination, all tissues were within normal histological limits. Follicular hyperkeratosis



(comedone formation) was not observed (Consumer Product Testing Company 1990d).

Skin Sensitization Glyceryl Laurate

The Cosmetic, Toiletry, and Fragrance Association (CTFA) provided the results of a 1975 study of the skin sensitization potential ofGiyceryl Lam·ate in a maximization test using guinea pigs.

Prior to study initiation, a preliminary irritation test (intradermal injection and topical application procedures) was performed using two groups of four males, respectively. In the intradermal injection test, the four animals were injected intradermally with Glyc~ryl Laurate (0.05% to 1% in 6% absolute alcohol/saline). Reactions described as faint, pink erythema predominated. In the topical application test, the other four males were tested with concentrations ranging from 5% to 25% in absolute alcohol. Scaling was observed in one guinea pig tested with 25% Glyceryl Laurate.

Ten guinea pigs (six males, four females) were tested in the maximization test. The animals were subjected to four sensitizing injections of 2% Glyceryl Laurate and then challenged with intradermal injections of 0.8% Glyceryl Laurate and topical applications of 25% Glyceryl Laurate. Four male guinea pigs served as controls. The grading scale for intradermal challenge reactions ranged from faint, pink erythema to deep, pink erythema. Topical challenge reactions were scored according to the following scale: ± (barely perceptible erythema) to++++ (erythema-breakdown of surface-necrosis). Positive reactions were not observed in either of the ten animals tested. Glyceryl Lam·ate was classified as a nonsensitizer (CTFA 1975).

Kabara (1984) studied the skin sensitization potential of a 20% Glyceryl Lam·ate emulsion in a guinea pig maximization test. To induce sensitization, I 0 animals were treated by intradermal injection in the shoulder region. At 7 days post injection, sensitization was boosted by placement of an occlusive patch over the injection site; an occlusive challenge patch was applied to the flank at 14 days post injection. Four additional guinea pigs were treated in a manner similar to that of the test group, except that the test substance was applied only during the challenge phase. Positive challenge reactions were observed in two test animals challenged with a 10% dilution of the test substance. No visible reactions were present in control animals challenged with a 10% dilution of the test substance or either test or control animals challenged with a 5% dilution.

A second challenge was initiated 7 days after the first. Positive reactions were observed in five test animals and two control animals challenged with a I 0% dilution of the test substance. Positive reactions were also observed in four test animals challenged with a 5% dilution of the test substance; no reactions were present in the control group. It was concluded that because positive reactions were observed in test and control groups (after first and second challenge), it is likely that irritation, and not

sensitization, was responsible for these observations (Kabara 1984).

Glyceryl Jsostearate

CTFA reported the results of a 1985 study of the skin sensitization potential of Glyceryl Isostearate using a guinea pig maximization test procedure. Eighteen guinea pigs (I 0 test, 4 treated controls, and 4 untreated controls; strain not stated) were used. During induction, the animals were injected intradermally (0.1-ml injections) in the shoulder region with 2.5% Glyceryl Jsostearate in a vehicle consisting of polyethylene glycol (PEG), microcrystalline cellulose (MCC), and Dobs/saline (dodecyl benzene sulfonate in physiological saline).

At 5 to 7 days after the last injection, an occlusive induction patch saturated with 100% Glyceryl Isostearate was maintained in contact with the injection site for 48 h. Intradermal injection reactions were scored according to the following scale: fp (faint pink erythema) to dp (deep pink erythema). The challenge phase was initiated 12 to 14 days after application of the induction patch. An occlusive challenge patch containing 50% Glyceryl lsostearate (in PEG and MCC) was applied to the skin for 24 h. Further challenges were made at weekly intervals, or longer, as required. Challenge reactions were scored according to the following scale at 24 and 48 h: 0 (no reaction) to 3 (marked erythema).

The four treated controls consisted of four guinea pigs that were tested according to the preceding study protocol, with the exception that Glyceryl Jsostearate was omitted only from the intradermal and covered patch induction procedures. The untreated control group consisted of four previously untreated animals that were challenged with Glyceryl Isostearate according to the procedure described earlier.

The results of the first challenge yielded one positive reaction at 24 h and two positive reactions at 48 h. Following the second challenge, positive reactions were not noted at 24 or 48 h. The slight sensitization reactions noted following the first challenge were confirmed by results of the third challenge (CTFA 1985).

Glyce1yl Citrate!Lactate!Linoleate!Oleate

Hiils AG (1996e) reported results of the skin sensitization potential of Glyceryl Citrate/Lactate/ Linoleate/Oleate using 20 guinea pigs. Ten guinea pigs served as controls. Any reactions, particularly those classified as erythema and edema, were assessed 30 and 54 h after the initiation of treatment. Undiluted Glyceryl Citrate/Lactate/Linoleate/Oieate was tested during induction phases I, II, and Ill (dermal application) because the undiluted material did not induce skin irritation in a preliminary test.

During the fourth week of testing, a "trigger concentration" was determined for initiation treatment on three guinea pigs that were the same ages as those in the main test. The undiluted test substance was administered (dermal application) as the highest, nonirritating concentration.



Glyceryl Citrate/Lactate/Linoleate/Oleate did not induce systemic effects or any adverse effects on body weight gain. At 30 h post application in induction phases I, II, and III, skin irritation was not observed in the 20 test animals or 10 vehicle-control animals. "Trigger" treatment with the undiluted test substance did not induce erythema or edema of the right rear flank at 30 or 54 h post application in test or control animals. Also, in patch tests, the vehicle did not cause skin reactions in animals of the test or control group. It was concluded that Glyceryl Citrate!Lactate!Linoleate/Oleate did not induce sensitization in guinea pigs (Hlils AG 1996e).

Glyceryl Rosinate Shao et al. ( 1993) conducted a study to investigate whetherthe

esterification of rosin with glycerol or other polyalcohols would alter the' allergenicity of rosin. The allergenicity of Glyceryl Rosinate was evaluated using three groups of 15 female Dunkin

Hartley guinea pigs. During induction, the first group (group I) received four

closed epidermal applications of8.3% glyceryl triabietate (GTA) in petrolatum (abietic acid, esterified to yield this compound, is the main component of rosin) on days 0, 2, 7, and 9 and two injections of Freund's complete adjuvant (FCA) on day 7. In the second group (group II), the induction procedure (same protocol) consisted off our closed epidermal applications of20% gum rosin and two injections of FCA. The control group was sham

treated. All three groups were challenged with the following: 0.93%,

2.8%, and 8.3% GTA; 10% glycerol esterified tall oil rosin (TORG), 20% gum rosin; and petrolatum vehicle control. Challenge patches (Finn chambers) were removed after 24 h, and reactions scored at 48 and 72 h post application. Study results (challenge phase, 72-h reading) are summarized below.

In group I, results indicated one positive reaction to 0.93% GTA; 2.8% GTA; 20% gum rosin; and petrolatum. The incidence of positive reactions in group II was as follows: 1 (8.3% GTA); 2 (10% TORG); 3 (0.93% and 2.8% GTA); and 9 (20% gum rosin). One positive reaction to 0.93% GTA and two positive reactions to 8.3% GTA were observed in the control group. Scores at 48 and 72 h were not significantly different from one another. It is important to note that in group II, the incidence of positive reactions to 10% TORG (two reactions) was less than that of 20% gum rosin (nine reactions). The esterification of rosin with glycerol, in effect, reduced the allergenicity of rosin. GTA was nonallergenic and did not cross-react with allergens in unmodified gum rosin (Shao et al. 1993).

This same laboratory evaluated the allergenicity of GTA and other esters of glycerol and abietic acid (Gafvert et al. 1994). Products formed from the esterification of abietic acid (mentioned in the preceding study) with glycerol include: glyceryl triabietate (GTA); glyceryl 1,2-diabietate (GDA1,2); glyceryl 1 ,3-diabietate (GDAu); and glyceryl 1-monoabietate (GMA).

The allergenicity of these compounds was evaluated according to the procedure in the preceding study using female Dunkin-

Hartley guinea pigs. Group I (14 animals) and Group II (15 animals) animals were induced with 3.3% GMA in petrolatum and 20% gum rosin in petrolatum, respectively. Petrolatum was applied to animals of Group III (control). The ani!Jlals were challenged with the following: GMA (0.37%, 1.1 %, and 3.3%); 5.7% GDA1,3; 5.7% GDA1,2; 8.3% GTA, and 10% unmodified gum rosin. Challenge reactions at 72 h post application were reported. All statistically significant findings are accompanied by p values.

In group I, GMA induced sensitization at concentrations of 0.37% (1 of 14 animals), 1.1% (4 of 14, p < .05), and 3.3% (6 of 14, p < .01 ). The incidence of sensitization reactions to GMA in group II was as follows: 0.37% GMA ( 1 of 15 animals), 1.1% (3 of 15), and 3.3% (2 of 15). No significant responses were noted when GDAu and GDA1.2 were tested on animals that were sensitive to GMA. Gum rosin induced sensitization in 8 of 15 animals (p < .01) in group II and in 1 of 14 animals in group I. No significant cross-reactivity with GMA was noted in animals that were sensitive to unmodified gum rosin. Neither GTA nor petrolatum induced sensitization in either of the three groups (Gafvert et al. 1994 ).

Phototoxicity and Photoallergy Glyceryl Isostearate

The phototoxicity and photoallergenicity potentials of G1yccryl Isostearate was evaluated using 20 albino guinea pigs. The back and sides of each animal were divided into the following six treatment areas: test material + UVA, test material + UVB, test material alone, positive control (8-methoxypsoralen) + UVA, UVB alone, and UVA alone. Doses of the test material and positive control (dose for each= 0.02 ml/cm2) were applied 30 min prior to irradiation. UV irradiations were performed using Philips tubes (TL 20W/09 forUVA and TL 20W/12 UV for UVB). Cutaneous reactions were evaluated at 24 h post treatment. Glyceryl Isostearate did not induce significant cutaneous reactions with or without UV irradiation. The positive control (8-methoxypsoralen) induced severe reactions (Unichema International 1997 a).

Immunologic Activity

Glyceryl Laurate

The effect of Glyceryl Laurate on delayed-type hypersensitivity to sheep erythrocytes was evaluated using mice. The four groups (1 0 mice per group) of female ICR mice used in the study were designated as treated (T; two groups), control (C), and normal (N). The mice in groups T and C were injected subcutaneously (s.c.) with 0.05 ml/mouse of sheep red blood cells (SRBCs) (3 x 109 cells/ml). Injections were made into the right hind footpads. The mice in group T were then immediately injected intraperitoneally (i.p.) with a saline suspension of Glyceryl Laurate, and group C mice were injected with saline alone. On day 4, mice of groups T, C, and N were injected (s.c.) in the left hind footpads with SRBCs (0.05 ml!mouse). Left footpad



thickness was measured with a caliper 24 h later. The i.p. administration of Glyceryl Lam·ate did not cause significant enhancement of the, immunological response. Mean footpad thickness was 4.20 ± 0.44 mm, compared to 4.23 ± 0.36 mm and 3.55 ± 0.23 mm for untreated mice and saline controls, respectively (Kabara et al. 1985).

The modulation of immune cell proliferation in vitro by Glyceryl Laurate was evaluated using lymphocytes obtained from murine spleens. Lymphocyte proliferation was stimulated at Glyceryl Lam·ate concentrations between w-s and 5 flg/ml per 5 x 105 lymphocytes. At concentrations greater than 5 /.-tg/ml, Glyceryl Lam·ate inhibited lymphocyte proliferation and blocked the proliferative effects of the lymphocyte mitogens, phorbol myristate acetate and concanavalin A, and the toxic shock syndrome toxin-] (potent T-cell mitogen). Furthermore, the ~;esults of experiments using purified immune cell subsets indicated that Glyceryl Lam·ate (0.1 flg/ml) optimally induced T-cell proliferation, but did not affect B cells. Glyceryl Laurate-induced T-cell proliferation was blocked by cyclosporin A (immunosuppressive drug) at concentrations as low as 20 ng/ml, suggesting that Glyceryl Laurate could be exerting its effect along the calcium-dependent inositol phospholipid, signal transduction pathway (Witcher, Novick, and Schlievert 1996).

In Vitro Hemolytic Activity Glyceryl Laurate

Kato et al. (1971) evaluated the hemolytic activity ofGlyceryl Lam·ate using sheep erythrocytes. The erythrocytes were washed with 0.86% NaCl and suspended in NaCJ solution. Glyceryl Laurate was dissolved or suspended in NaCl solution at several dilutions (starting with 1 mg/ml), and an equal volume of the reel blood cell suspension in NaCl was added. Hemolytic activity, expressed by the highest dilution in which hemolysis was observed, was determined after incubation for 4 h at 37°C. The highest dilution in which hemolysis was observed was a sevenfold dilution of the starting concentration of Glyceryl Laurate. Glyceryl Lam·ate had strong hemolytic activity.

GENOTOXICITY Glyceryl Citrate!Lactate/Linoleate/Oleate was evaluated for

its potential to induce reverse mutations in the following Salmonella typhimurium strains: TA 98, TA 100, TA 1535, and TA 1537. The Ames test (plate incorporation and preincubation methods) was used in this evaluation. Five concentrations of Glyceryl Citrate/Lactate/Linole-ate/Oieate (50 to 5000 flgl plate) were tested in triplicate both with and without metabolic activation. Tetrahydrofurane served as the solvent control, and the three positive controls were as follows: 2-nitrofluorene, sodium azide, and 9-aminoacridine. Glyceryl Citrate/Lactate/ Linoleate/Oieate was not mutagenic (all strains) in the plate incorporation test or the preincubation test either with or without metabolic activation (Hiils AG 1996f).

Glyceryl Rosinate and Glyceryl Hydrogenated Rosinate are esters of glycerin and acids derived from rosin, which is composed of diterpene resin acids. In studies on the mutagenicity of resin acids, only neoabietic acid (component of rosin) was mutagenic in the Ames/Salmonella assay (FDA 1'988).

CARCINOGENICITY

Glyceryl Stearate was tested for tumor promoting activity (Saffioti and Shubik 1963) on the clipped dorsal skin of 20 female Swiss mice. One week after a single application of 9,10-climethylbenz(a)anthracene (DMBA) (1% to 1.5% in mineral oil), 5% Glyceryl Stearate (in acetone) was applied to skin twice weekly. No tumors developed; slight epidermal hyperplasia at the site of application was noted.

Tumor Inhibition Glyceryl Laurate

Kabara et al. (1985) evaluated the in vitro antitumor activity of Glyccryl Lam·ate using two leukemia cell lines, L-5178Y and L-121 0. Leukemia cells were cultured ( 1.0 x 105 cells/ml, 48 h at 37°C) with various concentrations of the test substance, suspended in physiological saline containing 5.0% DMSO. Untreated cultures served as controls. The growth inhibitory effect was determined as the ratio of cell numbers in treated and control cultures at the end of the incubation period. Based on this ratio, the IC50 was obtained by probit diagramming analysis. The IC50

values were 50 and 62 mg/ml in L-1210 and L-5178Y cell lines, respectively. Thus, marked antitumor activity was demonstrated against both cell lines.

On the basis of the above results, these authors evaluated Glyceryl Laurate in a survival test using 5-week-old, female BDF1 mice implanted intraperitoneally with L-1210 leukemia cells (1.0 x 105 ceiJs/mouse ). A suspension of the test substance in saline was injected i.p. into each animal once daily for five consecutive days (first injection, 24 h after tumor transplantation). One group of mice received daily injections of 30 mg/kg, and the other, daily injections of 100 mg/kg. Control mice were injected with saline.

Study results indicated that Glyceryl Laurate was ineffective in prolonging the life span of tumor-bearing mice. Survival times for test mice were 9.83 clays (30 mg/kg dose group) and 9.66 days (l 00 mg/kg close group). The survival time for control mice was also 9.83 days. The investigators stated that the in vivo inactivity of Glyceryl Laurate could have been clue to the inappropriateness of the experimental conditions adopted, and that further tests should be performed using different routes of administration, dosages, or vehicles (Kabara et al. 1985).

In two earlier studies (Kato et al. 1969, 1971 ), the in vivo antitumor activity of Glyceryl Lam·ate in 5-week-old ddY mice (weights = 18 to 22 g) was evaluated using Ehrlich ascites tumor cells. In one study, 2 x 106 tumor cells were implanted i.p. into each of eight mice. Glyceryl Laurate was then administered i.p. daily for 5 successive clays at doses of 2.5 mg/mouse/day


GLYCERYL MONOESTERS 8I

(2 mice) and I 0 mg/mouse/day (2 mice). The four control mice were injected with tumor cells only. After 7 days, tumor growth and body weight gain were noted. Tumor growth was not observed in mice given either of the two doses. Survival was 27 and 24 days for the two mice dosed with 2.5 mg/day and 28 and >30 days for the two mice'dosed with 10 mg/day. Tumor growth in four control mice was marked and survival was I 3 to I 7 days. Glyceryl La urate inhibited tumor growth completely and increased the survival time of mice injected with tumor cells (Kato et a!. I 969).

In a study by Kato et a!. (1971 ), approximately one million tumor cells were implanted i.p. into I,2 test mice (two groups of six) and six controls, and a solution or suspension of Glyceryl Laurate in 0.86% NaCl solution was administered i.p. daily for 5 successive days. The two test groups received doses of 2.5 and I 0 mg/mouse/day, respectively, and control mice were injected with 0.2 ml of NaCl solution. After 7 days, tumor growth and body weight gain were noted. Tumor growth was marked in control mice (survival time = I 6 days). However, no tumor growth was observed in either group of test mice. Survival times for 2.5 mg/day and 10 mg/day test mice were 26 and > 29 days, respectively.

In an additional experiment, these authors evaluated the in vitro action of Glyceryl Laurate on Ehrlich ascites tumor. The hypothesis was that Glyceryl Laurate might have a specific affinity for the tumor cells, and, if strong enough, attack the cells. In vitro attack of the cells was measured using the viability of treated tumor cells. In the assay for viability, the viability of treated tumor cells (mixture of Glyceryl Laurate in phosphatebuffered saline with the tumor cell suspension) was determined by staining the cells with safranin dye. Glyceryl Laurate was tested at concentrations of 5, 50, and 500 [-Lglml. The percentage of dead cells in the mixture was determined by counting the number of cells microscopically. Cell death (I 00%) was noted at concentrations of 50 and 500 [-Lg/ml (Kato et a!. I 971 ).

REPRODUCTIVE AND DEVElOPMENTAL TOXICITY Studies on the reproductive and developmental toxicity of

the Glyceryl Monoesters reviewed in this report were not found in the published literature. Glyceryl Rosinate and Glyceryl Hydrogenated Rosinate are derived from rosin. As stated earlier, rosin is defined as the residue remaining when the volatile oil is distilled from turpentine or a product of the distillation, solvent extraction, or both, of the stumps or fallen trees of various species of Pinus. FDA (I988) reported that, following the administration of hexane extracts of Pinus ponderosa needles to mice by stomach tube, increased embryonic resorptions were observed. Recall that it is important to note that the following active components of the extracts tested, diterpene resin acids, were identified: pimaric acid, isopamaric acid, sandaracopimaric acid, palustric/levopimaric acid, abietic acid, dehydroabietic acid, and neoabietic acid. Abietic acid and dehydroabietic acid have been identified as main components of rosin.


Inhalation Toxicity Glyceryl Caprylate/Caprate is used in hair sprays. Jensen and

O'Brien ( 1993) reviewed the potential adverse effects of inhaled aerosols, which depend on the specific chemical species, the concentration, the duration of the exposure, and the site of deposition within the respiratory system. Particle size is the most important factor affecting the location of deposition.

The determination of the health consequences of exposure to an aerosol requires an analysis of the inhalation and deposition of the aerosol within the human respiratory system. The toxic action of an aerosol may be related to the number of particles, their surface area, or the mass deposited. Many occupational diseases are associated with the deposition of particles within a certain region of the respiratory tract.

The aerosol properties associated with the location of deposition in the respiratory system are particle size and density. The parameter most closely associated with this regional deposition is the aerodynamic diameter, d3 , defined as the diameter of a sphere of unit density possessing the same terminal setting velocity as the particle in question.

Many particles present in the air do not enter the respiratory tract because of the size-selective sampling of the nose and the mouth. Still others are removed in the upper respiratory tract. The concept of size-selective air sampling calls for measurement of particles in industrial aerosols of the size that are associated with a specific health effect. For chemical substances present in inhaled air as suspensions of solid particles or droplets, the potential hazard depends on the particle size as well as on mass concentration. The American Conference of Governmental Industrial Hygenists (ACGIH) has defined three particlesize-selective threshold limit values (PSS TLVs) (ACGIH I99I): inhalable particulate mass TLVs (IPM TLV s) for those materials that are hazardous when deposited anywhere in the respiratory tract; thoracic particulate mass TLVs (TPM TLVs) for those materials that are hazardous when deposited anywhere within the lung airways and the gas-exchange region; and respirable particulate mass TLVs (RPM TLVs) for those materials that are hazardous when deposited anywhere in the gas-exchange region (Jensen and O'Brien 1993).

The mean aerodynamic diameter of 4.25 ± I .5 [-Lm of respirable particles above may be compared with diameters of anhydrous hair spray particles of 60 to 80 [-Lm (typically, <I% are below I 0 {-Lm) and pump hair sprays with particle diameters of :=: 80 [-Lm (Bower I 999).

Skin Irritation Glyceryl Rosinate

The skin irritation potential of a lipstick containing I .0% Glyceryl Rosinate, as supplied, was evaluated using I2 volunteers (2 I to 45 years old). All subjects were in good heath and free of any visible skin disease or anomaly. The lipstick was crushed (to mix the inner and outer layers) and applied to an



occlusive patch. Patches (one per subject) covered with the lipstick were applied to the back and remained in place for 24 h. Reactions vyere scored 3 days later according to the following scale: 0 (no visible erythema) to 3 (severe erythema [very intense redness]). A new patch containing the test substance was reapplied to the same site on each subject and removed after 24 h. Reactions were scored after patch removal and 24 h later. The grading period was followed by a second new patch application (24 h), and reactions were scored at the same intervals. The lipstick containing 1.0% Glyceryl Rosinate did not elicit an irritation response (all scores = 0) in either of the 12 subjects tested (Biosearch, Inc. 1992a).

Skin Sensitization General

Human studies have indicated that the incidence of contact sensitization is dose dependent and that the induction of skin sensitization is dependent on the dose of a chemical per unit area of skin (Kimber, Gerberick, and Basketter 1999).

Glyceryl Law·ate and Glyceryl Linoleate Danisco Ingredients ( 1996), reported a study in which the

skin irritation and sensitization potential of Glyceryl Laur<1le and Glyceryl Linoleate was evaluated using 91 healthy volunteers (males and females, 18 to 65 years old) in a modified Draize repeat-insult patch test. The study was classified as single-blind. Patches consisted of a 5 em wide strip of Scanpor tape to which 10 "Finn-chambers" were fixed in pairs. The three glycerylmonoesters were tested at a concentration of 50% wjv in liquid paraffin. Glyceryl Linoleate (0.02 ml) was dispensed directly into individual Finn chambers. Glyceryl Laurate was heated to 60°C and 0.02 g was placed directly into individual Finn chambers; 0.02 ml liquid paraffin was dispensed onto a filter disc in the chamber. Liquid paraffin served as the negative control.

The 91 volunteers were divided into two groups, group 1 (39 subjects) and group 2 (52 subjects), respectively. In group 1, the first set of induction patches was applied to the upper back for 23 h and subsequent patch applications were 47 h in duration. The patch test schedule for these subjects was as follows: days I, 2, 4, 7, 9, 11, 14, 16 and 18. In group 2, 47-h induction patch applications were made according to the following schedule: days 1, 3, 5, 8, 10, 12, 15, 17, and 19. In both groups, induction patches were applied to the same site, unless a reaction stronger than mild erythema was observed. Reactions were scored after patch removal according to the following scale: 0 (no visible reaction) to 5 (bullous reaction).

During the challenge phase, initiated on day 35, patches were applied to new sites on the upper back for 47 h. Challenge reactions were scored at 1 and 49 h after patch removal. Classification of either test substance as irritating was based on 1 0% of the induction scores defined as> 1 (mild erythema). Sensitization was defined as a rapid i·esponse to challenge patch application, characterized by severe erythema and edema (usually with papules

and/or vesicles).

Seventeen of the 91 subjects withdrew for reasons either unrelated to treatment (16 subjects) or because the patch was painful (1 subject). Seventy-four subjects (64 women, 10 men) completed the study. Glyceryl Linoleate did not induce skin irritation or sensitization. However, Glyceryl Laurate indu~ed mild, erythematous reactions during induction in most of the subjects and questionable reactions during the challenge phase in seven subjects. During induction and challenge (1 and 49 h post removal) phases, reactions to Glyceryl Laurate ranged from 1 (mild erythema) to 2 (moderate erythema) (Danisco Ingredients 1996).

Glyceryl Law·ate, Glyceryl Myristate, and Glyceryl Oleate

Danisco Ingredients (1999f) reported results of a study in which the skin irritation and sensitization potential of Glyceryl Laurate, Glyceryl Myristate, and Glyceryl Oleate was evaluated in a single-blind study using 93 healthy volunteers (ages between 18 and 65 years). Ten of the original I 07 subjects withdrew for reasons unrelated to the conduct of the study. The repeat-insult patch test procedure (similar to procedure in preceding study) was a modification of the Draize test. Glyceryl Laurate was tested at a concentration of 25% in liquid paraffin oil, whereas Glyceryl Myristate and Glyceryl Oleate were each tested at a concentration of 50% in liquid paraffin oil. Liquid paraffin oil served as the control. Induction patches (Finn chambers on Scanpar tape) containing either of the three test substances or the control were applied to the upper back of each subject. The subjects were instructed to remove and discard the patches at the end of the 47-h contact period. This procedure was repeated (same sites) for a total of nine induction applications.

Test sites were evaluated prior to application of the next patch and 1 hour after patch removal on the last day of the induction phase according to the following scale: 0 (no visible reaction) to 5 (bullous reaction). Challenge patches were applied to the upper back (distant from induction site) of each subject on day 36. The patches were removed and discarded at the end of the 47-h contact period. Reactions were evaluated at 1 and 49 h after challenge patch removal.

Glyceryl Laurate (25% in liquid paraffin oil) induced moderate erythema (score= 2) in eight subjects during induction and in one subject during the challenge phase. Glyceryl Myristate and Glyceryl Oleate did not induce initation or sensitization at a concentration of 50% in liquid paraffin oil. The investigators concluded that the three test substances did not induce sensitization during induction or challenge phases (Danisco Ingredients 1999f).

Glyceryl Caprate

The skin sensitization potential of 15% Glyceryl Caprate in paraffinium per!. DAB 10 (pharmaceutical grade)was evaluated in a modified Draize assay using 63 subjects, 58 of whom completed the study. During induction, the test substance was applied (0.025 ml, occlusive patches-Finn chamber) to the scapular region of the back three times per week (on Mondays, Wednesdays, and Fridays) for a total of 10 applications. At the end of each



48-h period (72 h on weekend), patch~s were removed and sites rinsed with distilled water. Reactions were scored according to the following scale: 0 (no reaction) to 4 (erythema, edema, and bullae). A 12-day nontreatment period was initiated after reactions to the 1Oth induction patch were scored. At the end of the 12-day period, occlusive challenge patches were applied to new sites on the scapular back for 48 h. Challenge reactions were scored at 48 and 72 h post application. The test substance did not induce irritation or sensitization reactions in any of the subjects tested (International Research Services, Inc. 1995).

Glyceryl Rosinate Shao et al. (I 993) patch tested eight dermatitis patients who

had previously reacted to colophony (gum rosin) using Finn chambers with various rosins and rosin esters. Ten healthy subjects served as controls. Results indicated that the number of reactions to the rosin esters was lower, compared to the results for rosin. Five of eight patients had positive reactions to 10% tall oil rosin (in petrolatum), whereas four of eight patients had positive reactions to 20% glycerol-esterified tall oil rosin (in petrolatum). Also, seven of eight patients had positive reactions to 5% Portuguese gum rosin (in petrolatum) and three of eight patients had positive reactions to 20% glycerol-esterified gum rosin (in petrolatum). Additionally, neither of the eight subjects had positive reactions to glyceryl triabietate or petrolatum.

Positive reactions to each test substance ranged from+ (erythema and infiltration) to+++ (erythema, infiltration, and vesicles). Because abietic acid is a main component of rosin and is easily oxidized to form contact allergens, the concentrations of this acid in the following rosin esters and rosins that were tested are indicated as follows: Portuguese gum rosin (42% abietic acid); tall oil rosin (55%); glycerol-esterified gum rosin (0.3% ); and glycerol-esterified tall oil rosin (3.7% ). It is important to note that the methylated oxidation product of abietic acid, 15-hydroperoxyabietic acid methyl ester (contact allergen) induced positive reactions in six of the eight patients tested and that this incidence was lower than that reported for Portuguese gum rosin (seven of eight patients). The results of this study indicated that esterification with glycerol reduced the allergenicity of rosin (Shao eta!. 1993).

Gafvert et al. (1994) evaluated the allergenicity of the following compounds (in petrolatum) in patients with contact allergy to gum rosin, 5% Portuguese gum rosin (GR), 10% tall oil rosin (TOR), 20% glycerol-esterified gum rosin (GGR), 20% glycerol-esterified tall oil rosin (TORG), 5.4% glycerylmonoabietate (GMA), 9.5% glyceryl-1,2-diabietate (GDA1,2), and 9.5% glyceryl-1,3-diabietate (GDA1,3). GDA1,2, GDA1,3,

and GMA are products that result from the esterification of abietic acid with glycerol (mentioned in preceding study). Except for patch tests with GDA1,2 and GDA1,3 (6 patients), 12 patients were used in the evaluation of each compound. Patch tests (Finn chambers) involved the application of each compound to the skin for 48 h. Reactions were scored at 72 h post application.

Ten control subjects were patch tested according to the same procedure.

Results for the rosins and rosin esters were similar to those in the preceding study. Over half of the patients had reactions ( ++ to+++) to these compounds. Five of the 12 patients had positive reactions to GMA ( ++ to +++ ), and neither of the 6 patients had positive reactions to GDAu, or GDAu.· The patch testing of an additional patient with the latter two compounds also yielded negative results. No reactions were observed in the 10 healthy control subjects. This study confirmed the contact sensitization 'potential of rosin and rosin esters in patients with contact allergy to gum rosin and identified glyceryl-1-monoabietate as a contact allergen (Giifvert et al. 1994).

The Consumer Product Testing Company ( 1997) patch tested 53 subjects (males and females, 18 to 69 years old) with a test material consisting of 20% Purified Ester Gum-2-0ctyldodecyl Myristate and 80% white petrolatum (a.k.a. PEGMODWP-20). (Because Purified Ester Gum-2-0ctyldodecyl Myristate is a trade mixture consisting of 50% Glyceryl Rosinate and 50% Octyldodecyl Myristate, the effective concentration of Glyceryl Rosinate in the test material is 1 0%.) Forty-nine of the original 53 subjects completed the study; 4 withdrew for reasons that were unrelated to testing.

Approximately 0.2 ml of the test material (contains 10% Glyceryl Rosinate) was applied to the upper back, between the scapulae, of each subject on Mondays, Wednesdays, and Fridays for a total of 10 induction applications. Sites were covered with a semiocclusive patch immediately after each application of the test material. Non treatment periods of 24 h followed patch removals on Tuesdays and Thursdays. Saturday patch removals were followed by 48 h nontreatment periods. The induction phase was followed by a 2-week nontreatment period, after which a challenge patch was applied to the same site and a previously untreated site. Challenge reactions were scored at 24 and 48 h post application according to the following scale: 0 (no visible reaction) to 4+ (erythema and edema with vesiculation and ulceration). Induction reactions were also evaluated according to this grading scale.

One subject had a score of2+ (well-defined erythema, possible presence of barely perceptible edema) during induction and at 24 and 48 h during the challenge phase (at new test site, but not at original site). At 72 h, the same subject also had a challenge reaction of 3+ (erythema and edema) at the new test site, but not at the original site. None of the remaining 48 subjects had induction or challenge reactions. It was concluded that the test material did not have the potential for inducing skin irritation and/or sensitization in this study (Consumer Product Testing Company 1997).

Ivy Laboratories (1996) evaluated the sensitization potential of a foundation containing 4% Glyceryl Rosinate using 28 healthy adult volunteers (13 males and 15 females; 18 to 46 years old). Twenty-five subjects completed the study; 3 subjects were removed for reasons that were unrelated to application of the test substance. Patches were applied to the upper outer arm,



volar forearm, or to the back of each subject. During induction, approximately 0.1 ml of 0.25% aqueous sodium Iaury! sulfate (SLS) was f!pplied under an occlusive patch (secured with occlusive tape) that was removed after 24 h. The foundation (0.1 ml on semiopen induction patch) was then applied to the test site for 48 h (or 72 h, i.e., over the weekend). lf skin irritation was not observed at the time of patch removal, an occlusive patch containing 0.25% aqueous SLS was reapplied for 24 h. Patch removal was followed by reapplication of a fresh induction patch (semi-open) containing the foundation.

This sequence of SLS and test substance application was repeated for a total of five induction exposures. If irritation was observed at any time during induction, SLS pretreatment was discontinued and replaced with a 24 h nontreatment period between applications of the test substance. Following a 1 0-day nontreatment period, the challenge phase was initiated. Pretreatment with SLS was performed prior to challenge patch application. Approximately 0.1 ml of 5% aqueous SLS was applied, under an occlusive patch, to a fresh skin site for l h. After patch removal, a semiopen challenge patch containing 0.1 ml of the foundation was applied to the same site for 48 h. Challenge reactions were graded 1 h after patch removal and 24 h later according to the following scale: 0 (not sensitized) to 3 (strong sensitization, large vesiculobullous reaction).

Contact allergy was not observed in any of the subjects during either of the two grading periods (all scores = 0). It was concluded that the foundation containing 4% Glyceryl Rosinate did not possess a detectable contact-sensitizing potential and, hence, is not likely to cause contact sensitivity reactions under normal use conditions (Ivy Laboratories 1996).

The maximization assay described in the preceding study was also used to evaluate the sensitization potential of a blush containing 2% Glyceryl Rosinate. Twenty-seven healthy adult volunteers (11 males and 16 females; 18 to 56 years old) were tested. Contact allergy was not observed in any of the subjects during either of the two grading periods (all scores = 0). It was concluded that the blush containing 2% Glyceryl Rosinate did not possess a detectable contact-sensitizing potential and, hence, is not likely to cause contact sensitivity reactions under normal use conditions (Ivy Laboratories 1997).

The sensitization potential of a lip gloss containing 2.0% Glyceryl Rosinate was evaluated using 27 healthy adult volunteers (7 males, 20 females; 18 to 60 years old). Basically, the same maximization assay procedure (indicated above), was used with the following modifications: Patches were applied to the upper outer arm of each subject. During induction, the application of 0.1 ml of 1% aqueous SLS (occlusive patch) was followed by the application of 0.1 g of the test material (site covered with occlusive tape, referred to as induction patch). Prior to initiation of the challenge phase, the challenge site (new site on opposite arm) was pre-treated with 0.1 ml of 10% aqueous SLS (under occlusive patch) .. Pretreatment was followed by application of the test substance (same site) under an occlusive challenge patch secured with occlusive tape. Contact allergy was not observed

in any of the subjects during either of the two grading periods (all scores = 0), and there were no unusual or unexpected side effects. It was concluded that the lip gloss containing 2% Glyceryl Rosinate did not possess a detectable con(act-sensitizing potential and, hence, is not likely to cause contact sensitivity reactions under normal use conditions (Ivy Laboratories 1990).

Biosearch, Inc. (1992b) evaluated the skin irritation and sensitization potential of a lipstick containing 1% Glyceryl Rosinate, as supplied, using 78 volunteers ( 16 to 55 years old). Eleven of the original 89 subjects withdrew from the study for personal reasons. All subjects selected for the study were in good health and free of any visible skin disease or anomaly in the area of skin designated for patch testing. Approximately 0.15 g of the test substance was placed on an occlusive patch that was applied to the back of each subject for 24 h. Reactions were scored at 48 h post application according to the following scale: 0 (no visible erythema) to 3 (severe erythema [very intense redness]).

At the end of the grading period, a second patch was reapplied (same site) to each subject according to the same procedure. The test procedure was repeated on alternate days (Monday, Wednesday, and Friday) for a total of nine applications. Patches applied on Friday were removed on Saturday, and reactions were scored at 72 h post application. After a 2-week nontreatment period, a challenge patch containing the test substance was applied for 24 h to a new test site (adjacent to initial site) on each subject. Challenge reactions were scored at 48 and 72 h post application. Neither irritation nor sensitization reactions were observed in any of the subjects tested. The lipstick containing 1.0% Glyceryl Rosinate did not elicit a sensitization response (Biosearch, Inc. 1992b).

Glyceryl Hydrogenated Rosinate

The Consumer Product Testing Company (2000) patch tested sixty subjects (males and females, 17 to 75 years old) with a test material consisting of20% Hydrogenated Purified Ester Gum-2-0ctyldodecyl Myristate and 80% white petrolatum (a.k.a. Hydrogenated PEGMOD [20]). (Because Hydrogenated Purified Ester Gum-2-0ctyldodecyl Myristate is a trade mixture consisting of 50% Hydrogenated Glyceryl Rosinate and 50% Octyldodecy I Myristate, the effective concentration of Hydrogenated Glyceryl Rosinate in the test material is 1 0%.) Fifty-one of the original 60 subjects completed the study, because 9 withdrew for reasons that were unrelated to testing.

A semi occlusive patch containing approximately 0.2 ml of the test material (contains 10% Hydrogenated Glyceryl Rosinate) was applied to the upper back, between the scapulae, of each subject on Mondays, Wednesdays, and Fridays for a total of nine, 24-h induction applications. Nontreatment periods of 24 h followed patch removals on Tuesdays and Thursdays. Saturday patch removals were followed by 48 h nontreatment periods. The induction phase was followed by a 2-week non treatment period, after which a challenge patch was applied to a new test site, but not to the original site. Challenge reactions were scored at


GLYCERYL MONO ESTERS 85

24 and 72 h post application according to the following scale: 0 (no visible skin reaction) to 4 (severe erythema, possible edema, vesiculation, bullae and/or ulceration). The same scale was also used to evaluate induction reactions.

Neither skin irritation nor sensitization was observed in any of the subjects tested. It was concluded that the test substance did not not have the potential for inducing dermal irritation or allergic contact sensitization in this study (Consumer Product Testing Company 2000).

Glyceryl Rosinate and Glyceryl Hydrogenated Rosinate

These are esters of glycerin and acids derived from rosin. In its reviews of rosin in color additive lakes, the FDA assessed the safety of various rosins (FDA 1988, 1994a, 1994b ). The agency's findings are summarized below.

Although rosin has a history of use as a skin salve and as a soap, there were no toxicological data (e.g., from dermal in·itation studies) that would support the safe use of rosin in contact with the skin or mucous membranes (e.g., in the lip area). Gum and wood rosins may be safely ingested; however, there are no data that support the safe use of rosin(s) as a substratum in color additive lakes intended for external uses (FDA 1988). ln a more recent toxicology review, after considering that the "worst case" estimate for rosin content in lipsticks is 7.7% and that a more realistic estimate for lipstick rosin content is 0.6%, it was determined that, based on human patch test results, there appears to be little risk of irritant reactions due to rosin contained in

lipsticks (FDA 1994a). Furthermore, data submitted to FDA in 1994 indicated that

lipsticks, blush, lipliner pencil, and nail polish containing rosinated Jakes did not induce skin irritation in human subjects. Specifically, no skin irritation was observed when 197 subjects were patch tested (48-h single application) with blush products containing rosinated color additive lakes (9.3%) or when 10 subjects were tested with a lipstick product containing 1.07% rosinated color additive lakes in a phototoxicity test. Thus, FDA concluded that rosinated color additive lakes in cosmetic products at concentrations up to 9.3% do not present a health hazard due to irritation (FDA 1994b ).

Skin irritation reactions to rosin/colophony have been reported; however, the intensity of these reactions is dependent upon the test concentration as well as the particular rosin that is being tested. In a human study on 60% colophony (Portuguese gum rosin), patch test results indicated that skin irritation could have been observed. However, in other studies, no evidence of skin irritation was found in more than 2300 subjects tested with 60% rosin or in 1132 patients patch tested with 20% rosin. Additionally, a number of commercially available, structurally modified rosin acids have been reported to induce dermal irritation. Most have an irritation threshold at concentrations greater than 10% (FDA 1994a).

FDA concluded that rosin/colophony can be classified as a moderate sensitizer. Sensitization to gum rosin exhibits a doseresponse relationship (0.00 1% to 20% ), indicating that sensiti-

zation can be minimized by reducing the concentration (details from the original study referenced in FDA's review of rosin are included in the next paragraph). It is important to note that positive allergic responses to rosin have been confirmed in both animal and human studies. Because of the allergenicity of rosin in human subjects, this compound is included in the standard 23-compound allergic contact dermatitis screen that is used by dermatologists (FDA 1994a). '

FDA also considered results of a study by Karl berg ( 1988) using the method of Fregert (1981) in which patients with suspected 'rosin-allergy were patch tested with serial dilutions of Portuguese gum rosin in petrolatum according to the internationally accepted method for diagnosis of contact allergy by Fregert (1981 ). Finn chambers and Scanpor surgical tape were used. Patches were removed after 48 h of contact and reactions were scored at 72 h post application.

Twelve patients were tested with Portuguese gum rosin at concentrations ranging from 0.001% to 20%. Another group of 12 patients who had +++ reactions to 20% gum rosin in an earlier study was retested with two different preparations of Portuguese gum rosin (one in petrolatum) at concentrations ranging from 0.001% to 10%.

A clear dose-response relationship (with a maximum response at doses of 1 0% to 20%) was observed in the serial dilution test with 0.001% to 20% gum rosin (wjw) in petrolatum. The author stated that these results imply that a concentration of 10% gum rosin is worth considering for routine testing. The incidence of positive reactions to two different preparations of gum rosin in the second group of 12 patients is summarized as follows: 0.001% gum rosin (0 to 1 patient), 0.01% gum rosin (2 to 3 patients), 0.1% gum rosin (8 patients), 1% gum rosin (12 patients), and 10% gum rosin (10 to 12 patients). In theresults for 10% gum rosin, all but 2 patients were tested with both preparations of gum rosin (Karlberg 1988).

Overall, FDA concluded that there is little or no potential for dermal irritation reactions due to rosin at the concentrations used in lipsticks containing rosin lakes. Therefore rosin, at the concentrations that can be present in lipstick containing color additive rosin Jakes, does not present a health hazard due to irritation. OCAC reports that unmodified rosin is a moderate sensitizer and can induce allergic reactions in sensitized individuals. At the concentration of rosin that can be present as a component of color additive lakes (up to 7%), rosin can cause sensitization in unsensitized individuals. It is possible that rosin is bound during the color laking process and is not available to induce sensitization. However, no information was available regarding the skin absorption and subsequent skin sensitization potential of rosin contained in color additive lakes. FDA recommended further studies be undertaken to address this issue (FDA 1994a).

FDA amended its conclusion after human skin sensitization data on various cosmetic products containing rosinated Jakes of D&C Red No.6, D&C Red No.7, and D&C Red No. 34 at several different concentrations were received. FDA concluded that



the use of rosin as a substratum in rolor additive lakes is safe, up to rosinated color additive concentrations of 9.0% in cosmetics products. This conclusion was b~1sed on the observation that no skin sensitization or photoallergic reactions to cosmetic formulations containing rbsinated ~olor additives at concentrations up to 9.0% were noted in human subjects. The human data included a photoallergy test using 312 subjects and a composite of repeat insult patch tests on a total of 2,381 subjects (FDA 1994b ).

FDA also included in its consideration the components of rosin. Abietic acid and dehydroabietic acid, resin acids, are the main component of rosin. Abietic acid was not considered a contact allergen and the risk of resin acids inducing contact sensitivity in workers exposed to tall oil-containing products was considered minimal (FDA 1988).

The later review noted that oxidation products of abietic and . dehydroabietic acid (which can be formed during storage) have been found to be allergenic. Hydrogenation of rosin acid reduced the allergenic potency of these oxidized gum rosin. There may be cross sensitization between several oxidized rosin acids. The oxidation of rosin acids might be .necessary in order to induce immunologic properties (FDA 1994a).

The FDA review also considered that peroxides and hydroperoxides of rosin acids can contribute to the sensitization potential of rosin. Specifically, the test results for nine synthesized oxidation products of abietic acid and other rosin acids indicated that 7-oxodehydroabietic acid; 13,14-epoxy abietic acid; and 8,12-peroxidodihydroabietic acid, (strongest sensitizer of the three) are moderate sensitizers. Furthermore, the sensitization potential of a mixture of oxidation products from the polar fraction was found to be as strong as that of the peroxido compound. Methyl ester, keto, hydroxy, and hydroxylated unsaturated ketone derivatives were weak to poor sensitizers (FDA 1994a).

Phototoxicity Biosearch, Inc. (1992c) evaluated the phototoxicity of a lip

stick containing 1.0% Glyceryl Rosinate, as supplied, using 10 volunteers (17 to 55 years old). All subjects were in good health and free of any visible skin disease or anomaly in the area of skin designated for patch testing. Subjects on medication (especially medications suspected of causing photobiological reactions or medications with the potential for modifying the inflammatory response) were excluded. The subjects were classified as Fitzpatrick skin types I, II, and III. The degree of skin pigmentation did not significantly influence responses to UV light or interfere with the scoring of skin reactions. The test substance was applied (approximately 20 mg/site) to two sites on the back of each subject and spread to cover the areas uniformly. One of the test sites was irradiated with 0.5 MED (minimal erythemal dose, in seconds) ofUVA and UVB light (continuous spectrum in UVA and UVB regions, 290 to 400 nm) between 30 and 60 min after application of the test substance. The MED was defined as the shortest exposure time at which erythema was first observed 20 ± 4 h after exposure. Irradiation with UVA and UVB light was followed by exposure to a total of 14 Jou1es/cm2 of UVA.

A 2 mm thick WG-345 Schott filter was interposed to eliminate UVB (290 to 320 nm) radiation from the ultraviolet source.

Reactions were scored at 24, 48, and 72 h post inadiation according to the following scale: 0 (no visible erythema) to 3 (severe erythema [very intense redness]). The second site to which the test substance had been applied was not irradiated and served as an irritation control. A third site served as the untreated, irradiated control. Skin irritation was not obs'erved (score = 0) at control or irradiated sites in either of the ten subjects tested. The lipstick containing 1.0% Glyceryl Rosinate did not elicit a phototoxicity response (Biosearch, Inc. 1992c).

Photoallergenicity

Biosearch, Inc. (1992d) evaluated the photoallergenicity of a lipstick containing 1% Glyceryl Rosinate, as supplied, using 26 volunteers ( 17 to 55 years old). Four of the original 30 subjects withdrew for personal reasons. All subjects were in good health and free of any visible skin disease or anomaly in the area of skin designated for patch testing. Subjects on medication (especially medications suspected of causing photobiological reactions or medications with the potential for modifying the inflammatory response) were excluded. Skin types were variable and the degree of skin pigmentation did not significantly influence responses to UV light or interfere with the scoring of skin reactions. During the induction phase, each of the subjects received six applications of the test substance over a period of 3 weeks. For each application, approximately 0.15 g of the test substance was placed on an occlusive patch that was applied to the back for 24 h. Patches were applied on Tuesdays and Thursdays. After patch removal, each site was exposed to 2.0 MEDs of UVB radiation and 4 Joules/cm2 ofUVA radiation. The subjects were instructed to keep the back covered throughout the study to avoid exposure to natural or artificial sunlight. The challenge phase was initiated 18 days after the last induction exposure. Challenge patches containing the test substance were applied to two new, adjacent test sites for 24 h. After patch removal, reactions were scored according to the scale indicated in the preceding study.

One of the test sites was then exposed to a combination of0.5 MED ofUVB and 4 Joules/cm2 ofUVA light. The other site was not exposed to UVA light and served as the initation control. The UV light control site was defined as an additional site that was not exposed to the test substance but was irradiated with 0.5 MED of UVB and 4 Joules/cm2 of UVA light. Challenge sites were scored at 24, 48, and 72 h post-irradiation. No reaction (score= 0) was observed at control or test sites on any of the 26 volunteers tested. The lipstick containing 1.0% Glyceryl Rosinate did not elicit a photoallergy response (Biosearch, Inc. 1992d).

Case Reports

A strong positive reaction was observed when a 35-year-old female patient with itchy, facial erythema was tested with 0.01% glyceryl monoisostearate. Reportedly, the itchy, facial erythema



resulted from the use of a foundation s;ontaining 1.77% glyceryl diisostearate. It is important to note that Glyceryl Monoisostearate was one of the impurities detect'ed in glyceryl diisostearate (Tanaka, Shimizu, and Miyakawa 1993).

Glyceryl Monoisostearate (0.01% in petrolatum) induced++ reactions (at 48 and 72 h) in an' 18-year-old girl with a history of what was described as lip cream dermatitis (Hayakawa et al. 1987).

SAFETY INFORMATION ON ARACHIDONIC ACID Information from the CIR Final Report on the safety of

Arachidonic Acid in cosmetics (Andersen 1993) is summarized below.

Arachidonic Acid is an essential, polyunsaturated, fatty acid that is used as a surfactant-cleansing agent and a surfactantemulsifying agent in cosmetic formulations. Arachidonic Acid is a liquid at room temperature, is soluble in alcohol, ether, and water, and absorbs in the ultraviolet B (UVB) range. Arachidonic Acid is well absorbed from the gastrointestinal tract and the circulatory system, it distributes rapidly into the lipid compartment of the body, and is rapidly converted to phospholipid by the liver. Arachidonic Acid can be metabolized by three different pathways: the cyclooxygenase, lipoxygenase, and cytochrome P450 systems.

Arachidonic Acid metabolites are involved in the inflammatory process. A chronic cellular imbalance of Arachidonic, y-linolenic, and eicosapentaenoic acids, and of their respective eicosanoid derivatives, may have major health implications. Arachidonic Acid may alter the cutaneous immune response.

ln a study in which Arachidonic Acid was applied to the pinnae of mice, an increase in pinnal thickness was observed. Microscopic effects were also observed throughout the study. Application of Arachidonic Acid to mouse skin produced edema and inflammation, with high doses possibly causing ulceration of the skin.

Arachidonic Acid did not produce teratogenic effects. Exogenous Arachidonic Acid appeared to help prevent the teratogenic effects caused by hyperglycemia and phenytoin. Subcutaneous administration to pregnant diabetic rats significantly reduced neural tube defects, cleft palate, and micrognathia. Arachidonic Acid has also dose-dependently reversed antimasculinization caused by a number of compounds. However, indomethacin has been found to stop the reversal of teratogenic effects by Arachidonic Acid.

Arachidonic Acid has mutagenic potential. Arachidonic Acid has increased the frequency ofTGr colonies, phagocyte-induced SCEs, chromosomal aberrations, thioether synthesis, MAL number, and the incorporation of [3H]thymidine/mg cellular DNA.

In 24 h single insult patch tests, a formulation containing 0.04% Arachidonic ACid was not an irritant.

The CIR Expert Panel recognized that dermal absorption data were lacking and that such data were necessary before a deter-

mination of safety can be made. And based on the results of those 'studies, still further data may be needed. Because Arachidonic Acid may be involved in UV light-induced cutaneous immune suppression, immunomodulatory data may be requested (dependent on the results of the dermal absorption studies). In addition to immunomodulatory data, carcinogenicity, photocarcinogenicity, and human irritation, sensitization, and photosen-sitization data may also be requested. '

Accordingly, the CIR Expert Panel found that the safety of this ingredient has not been documented and substantiated for cosmetic product use. The additional data needed were described as follows:

1. Dermal absorption data

Based on the results of the absorption studies, the Panel indicated there may be a need for the following data:

2. lmmunomodulatory data 3. Carcinogenicity and photocarcinogenicity data 4. Human irritation, sensitization, and photosensitization data

(Andersen 1993)

SUMMARY The safety of the following 43 Glyccryl Monoesters in cos

metics is reviewed in this report: Glyceryl Laurate, Glyceryl Laurate SE, Glyceryl Laurate/Oleate, Glyceryl Adipate, Glyceryl Alginate, Glycery1 Arachidate, Glyceryl Arachidonate, Glyceryl Behenate, Glyceryl Caprate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Citrate!Lactate!Linoleate/ Oleate, Glyceryl Cocoate, Glyceryl Collagenate, Glyteryl Erucate, Glyceryl Hydrogenated Rosinate, Glyccryl Hydrogenated Soyate, Glyceryl Hydroxystearate, Glyce1yl Isopalmitate, Glyceryl Jsostearate, Glyceryl Isostearate/Myristate, Glyceryl Isostearates, Glyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Montanate, Glyceryl Myristate, Glyceryl Isotridecanoate/Stearate/ Adipate, Glyceryl Oleate SE, Glyceryl Oleate/Elaidate, Glyceryl Palmitate, Glyceryl Palmitate/ Stearate, Glyceryl Palmitoleate, Glyceryl Pentadecanoate, Glyceryl Polyacrylate, Glyceryl Rosinate, Glyceryl Sesquioleate, Glyceryl/Sorbitol Oleate/Hydroxystearate, Glyceryl Stearate/ Acetate, Glyceryl Stearate/Maleate, Glyceryl Tallowate, Glyceryl Thiopropionate, and Glyceryl Undecylenate.

According to one source, Glyceryl Monoesters are not pure monoesters, but are mostly mixtures with mono-, di-, and triesters in a ratio of approximately 4:4:2, respectively. Another source indicates that the guaranteed purity of commercial and conventional Monoglyceride (Glyceryl Monoester) is a minimum of 90%, meaning that impurities account for a maximum of 10% of the composition. The results of impurities analyses of 14 Glyceryl Monoesters indicated that only one, Glyceryl Palmitate/Stearate, contained (mono)glycerol diester at a concentration of 1.2%.

UV spectral analyses of 14 Glyceryl Monoesters indicated maximum absorbance at 238 or 239 nm.



Glyceryl Monoesters are used. mostly as skin conditioning agents-emollients and/or surf~ctant-emulsifying agents in cosmetics. Frequency of use data provided by FDA in 1998 indicate that of the 43 ingredients in this safety assessment, the following 16 are used in ~osmetics: Glyceryl La urate, Glyceryl Alginate, Glyceryl Arachidonate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Cocoate, Glyceryl Hydroxystea~·ate, Glyceryl Isostearate, Glyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Palmitate, Glyceryl Myristate, Glyceryl Polyacrylate, Glyceryl Rosinate, and Glyceryl Undecylenate.

Concentration of use data reeeived from the cosmetics industry in 1999 indicate that Glyceryl Monoesters are used at concentrations up to 12% in cosmetic products.

Glyceryl Monoesters have also been approved by FDA for · use as direct or indirect food addtives. The Food Protection Committee of the National Academy of Sciences National Research Council Food and Nutrition Board concluded that there appears to be no reason to question the safety of mono-, di-, or triglycerides of lauric acid (i.e., Glyceryl ,La urate, Glyceryl Dilaurate, or Glyceryl Trilaurate [Trilaurin]) as food additives.

Glyceryl Monoesters (monoglycerides) are metabolized to free fatty acids and glycerol, both of which are available for the resynthesis of triglycerides.

Glyceryl Laurate enhanced the penetration of drugs through cadaverous skin and hairless rat skin in vitro.

Lauricin (registered trademark forGlyceryl La urate) has been described as having a wide spectrum of antimicrobial activity against diverse microbial species (viruses, fungi, molds, yeasts, and bacteria included).

A low-grade irritant response was observed following inhalation of an aerosol containing 10% Glyceryl Lam·ate by test animals.

An LD50 of > 20,000 mg/kg was reported for rats dosed orally with Glyceryl Laurate. In other studies, neither Glyceryl Isosteararate nor Glyceryl Citrate/Lactate/Linoleate/Oleate induced toxicity in rats that received a single oral dose of 2000 mglkg. Similar results were reported in an acute dermal toxicity study in which 2000 mg/kg Glyceryl Citrate/Lactate/ Linoleate/Oleate was administered to rats.

Undiluted, Purified Ester Gum-2-0ctyldodecyl Myristate (contains 50% Glyceryl Rosinate and 50% octyldodecyl myristate) was not toxic (LD50 > 5 g/kg) when administered orally to fasted Wistar albino rats (five males, five females; weight range 220 to 292 g). None of the animals died.

A no-effect level of 280 mg/m3 was reported for Glyceryl Laurate in a short-term inhalation toxicity study involving rats. Rats were subjected to 14 1-hour exposures during a 3-week period. Neither gross nor microscopic lesions were noted in rats fed 25% Glyceryl Lam·ate in another short-term (10 weeks) study.

No test substance-related gross or microscopic changes were observed in albino rats fed a mixture of mono-, di-, and triglycerides containing 40% to 45% Glyceryl Laurate for two years.

Glyceryl Laurate had strong hemolytic activity in an in vitro assay using sheep erythrocytes.

Glyceryl Laurate, Glyceryl Isostearate, or Glyceryl Citrate/ Lactate/Linoleate/Oleate were not classified as ocular irritants in rabbits. Undiluted, purified Ester Gum-2-0ctyldodecyl Myristate (contains 50% Gl)'ceryl Rosinate and 50% octyldodecyl myristate) also was not irritating to the eyes of rabbits.

Undiluted Glyceryl Lam·ate induced minor erythema and edema when applied (occlusive patches, single application) to inta.ct skin of rabbits. In another study, single occlusive patch applications of 20% Glyceryl Lam·ate emulsion to abraded and intact skin caused moderate skin irritation in rabbits.

Overall, Glyceryl Isostearate was classified as nonirritating to the skin of rabbits in a study in which single, semiocclusive patch applications were made to intact skin. The most severe reaction (moderate irritation) did not clear until day 5 post removal. Glyceryl Isostearate was also classified as nonirritating to the skin of rabbits in another study in which single occlusive patch applications were made to intact and abraded skin sites.

A Pll of 3.40 (potential for severe irritation-warning label may be considered) was reported in an occlusive patch test evaluating the skin irritation potential of undiluted, Purified Ester Gum-2-0ctyldodecyl Myristate (contains 50% Glyceryl Rosinate and 50% octyldodecyl myristate) in rabbits. Follicular hyperkeratosis (comedone formation) was not observed in another study in which the same undiluted test substance was applied to the ears of rabbits.

Neither erythema nor edema was observed in rabbits after semiocclusive patches containing heated Glyceryl Citrate/ Lactate/Linoleate/Oleate (single application) were applied to intact skin. In another study, Glyceryl Citrate/Lactate/Linoleate/ Oleate (single applicatioin) induced clearly circumscribed erythema and very mild edema when applied to intact skin of rabbits. All reactions had cleared by day 10 post application.

The skin sensitization potential of Glyceryl La urate was evaluated in the maximization test. Guinea pigs were subjected to four sensitizing injections of 2% Glyceryl La urate and then challenged with intradermal injections of0.8% Glyceryl Lam·ate and topical applications of 25% Glyceryl Laurate. No positive reactions were observed. In another maximization test, skin sensitization was induced in 2 of I 0 guinea pigs challenged with a 10% dilution of20% Glyceryl La urate emulsion. When a second challenge was initiated 7 days after the first, positive reactions were observed in five animals. Positive reactions were also observed in four animals challenged with a 5% dilution of 20% Glyceryl Lam·ate emulsion. Because positive reactions were also noted in the control group after the first and second challenge, the results were attributed to skin irritation (but not sensitization) effects of the test substance.

Glyceryl Isostearate was also evaluated in the maximization test. After induction, ten guinea pigs were challenged with 50% Glyceryl Isostearate in polyethylene glycol (PEG) and microcrystalline cellulose (MCC). Two additional challenges were also conducted. The first challenge yielded one and two positive



reactions (all slight reactions) at 24 and 48 h, respectively. These results were confirmed by reaction~ observed after the third challenge.

The sensitization potential of Glyceryl Citrate/Lactate/ Linoleate/Oleate in 20 guinea pigs was evualated using the Buehler method. Following the dermal application of undiluted test substance during induction and challenge phases, no evidence of irritation or sensitization was observed.

The reaction of rosin with glycerol to form two esterification products (glyceryl triabietate [GTA] and glycerol esterified tall oil rosin [TORG]), in effect, reduced the allergenicity of rosin. GTA results from the esterification of glycerol with abietic acid, the major component of rosin. The incidence of positive challenge reactions in 15 guinea pigs tested was as follows: 1 (8.3% GTA), 2 (10% TORG), 3 (0.93% and 2.8% GTA), and 9 (20% gum rosin). Glyceryl diabietate and g1yceryl monoabietate induced either the same incidence or a higher incidence of sensitization in other experiments (similar test groups) in the same study.

No evidence of significant cutaneous reactions, with or without UV irradiation, was found when the photoxicity and photoallergenicity potential of Glyceryl Isostearate was evaluated using 20 guinea pigs.

In a study (using mice) investigating the effect of Glyceryl Laurate on delayed-type hypersensitivity to sheep erythrocytes, the test substance did not cause significant enhancement of the immunological response. In another study using lymphocytes from murine spleens, Glyceryl Laurate-induced T-celJ proliferation was blocked by cyclosporin A (immunosuppressive drug) at concentrations as low as 20 ng/ml. These results suggest that Glyceryl Laurate could be exerting its effect along the calciumdependent inositol phospholipid, signal transduction pathway.

In Ames plate incorporation and preincubation mutagenicity tests, Glyceryl Citrate!Lactate!Linoleate/Oleate was not mutagenic (with or without metabolic activation) to the following Salmonella typhimurium strains: TA 98, TA 100, TA 1535, and TA 1537. In studies on the mutagenicity of resin acids, only neoabietic acid (component of rosin) was mutagenic in the Ames/Salmonella assay. Glyceryl Rosin ate and Glyceryl Hydrogenated Rosinate are esters of glycerin and acids derived from rosin, which is composed of diterpene resin acids.

Marked antitumor activity against two leukemia cell lines in vitro was observed in the presence of Glyceryl Lam·ate. A follow-up study to the preceding assay indicated that Glyceryl Laurate (i.p. injection, saline suspension) was ineffective in prolonging the lifespan of tumor-bearing BDF 1 mice that had been implanted i.p. with L-121 0 leukemia cells. Doses of 30 and 100 mg/kg were injected daily for 5 consecutive days. In other experiments, the antitumor activity of Glyceryl La urate against Ehrlich ascites tumor cells was demonstrated both in vivo and in vitro. In the two in vivo studies, Glyceryl Laurate (in saline) was injected i.p. into ddY mice that had been implanted i.p. with Ehrlich ascites tumor cells. Doses of 2.5 and 10.0 mg/mouse were injected daily for 5 successive days. Test results (both studies) indicated

no tumor growth and increased survival time (compared to controls) at both doses.

The tumor promoting activity of Glyceryl Stearate on the clipped dorsal skin of Swiss mice was evaluated. One week after a single application of 9,10-dimethylbenz(a)anthracene (DMBA) (1% to 1.5% in mineral oil), 5% Glyceryl Stearate (in acetone) was applied to skin twice weekly. No tumors dev~Joped; slight epidermal hyperplasia at the site of application was noted.

Following the administration of hexane extracts of Pinus ponderosa needles to mice by stomach tube, increased embryonic resorptions were observed. Glyceryl Rosinate and Glyceryl Hydrogenated Rosinate are esters of glycerin and acids derived from rosin, and rosin is obtained from trees of various species of Pinus.

Glyceryl Laurate, Glyceryl Linoleate, and Glyceryl Palmitate were each tested at a concentration of 50% wjv, in liquid paraffin, in a repeat insult patch test (RIPT) (Finn chambers) involving 91 healthy human subjects. Glyceryl Linoleate did not induce skin irritation or sensitization in the 74 subjects who completed the study. Glyceryl Laurate induced mild, erythematous reactions during induction in most of the subjects and questionable reactions in seven subjects during the challenge phase. Reactions ranged from mild to moderate erythema (score = 2) during induction and challenge phases.

The skin irritation and sensitization potential ofGJyceryl Laurate, G1yceryl Myristate, and G1ycery1 Oleate was evaluated in a second RIPT (Finn chambers) using 107 healthy subjects, 93 of whom completed the study. Glyceryl Laurate was tested at a concentration of 25% in liquid paraffin oil, whereas Glyceryl Myristate and Glyceryl Oleate were tested at a concentration of 50% in paraffin oil. Glycery1 Laurate induced moderate erythema (score= 2) in eight subjects during induction and in one subject during the challenge phase. Glyceryl Myristate and Glyceryl Oleate did not induce irritation or sensitizatiion. Neither of the three test substances was considered a sensitizer. In another study, Glyceryl Caprylate (15%) did not induce skin irritation or sensitization in an RIPT involving 63 healthy subects, 58 of whom completed the study.

Two case reports indicated skin reactions to two cosmetic products containing Glyceryl Isostearate, as well as positive patch test reactions to this ingredient.

Skin irritation was not observed in 12 healthy volunteers patch tested (occlusive patches) with a lipstick containing 1.0% Glyceryl Rosinate. Neither skin irritation nor sensitization was observed in 78 healthy volunteers patch tested (occlusive patches) with the same product in a repeated insult patch test.

The contact sensitization potential of three product formulations containing Glyceryl Rosinate was evaluated in three maximization assays (healthy human subjects), respectively. Results were negative for the following three study groups: foundation containing 4.0% Glyceryl Rosinate (25 subjects), blush containing 2.0% Glyceryl Rosinate (27 subjects), and lip gloss containing 2.0% Glyceryl Rosinate (27 subjects).



Skin irritation and sensitization were observed in one of 49 subjects patch tested (RIPT, semiocclusive patches) with a material consisting of 20% Purified Ester Gum-2-0ctyldodecyl Myristate and 80% white petrolatum (a.k.a. PEGMODWP-20). (Because Purified 'Ester Gum-2-0ctyldodecyl Myristate is a trade mixture consisting of 50% Glyceryl Rosinate and 50% Octyldodecyl Myristate, the effective concentration of Glyceryl Rosinate in the test material is 1 0%.) The challenge reaction was observed at the original test site, but not at the new site. It. was concluded that the positive reaction observed was unique to that individual.

Neither skin irritation nor sensitization was observed in any of the 51 subjects patch tested (semiocclusive patches) with a material consisting of 20% Hydrogenated Purified Ester Gum-2-0ctyldodecyl Myristate and 80% white petrolatum· (a.k.a. Hydrogenated PEGMOD [20]). (Because Hydrogenated Purified Ester Gum-2-0ctyldodecyl Myristate is a trade mixture consisting of 50% Hydrogenated Glyceryl Rosinate and 50% Octyldodecyl Myristate, the effective concentration of Hydrogenated Glyceryl Rosinate .in the test material is 1 0%.) The subjects were challenged at a new test site, but not at the original site.

Phototoxicity was not induced in a group of 10 healthy volunteers tested with a lipstick containing 1.0% Glyceryl Rosinate. Patches were not applied to test sites. Similarly, photoallergenicity was not induced in a group of 26 healthy volunteers patch tested (occlusive patches) with the same product in a repeat insult patch test.

Data on 12 patients suspected of having gum rosin allergy indicated that sensitization to Portuguese gum rosin exhibited a dose-response relationship (0.001% to 20%). In the same study, the incidence of positive reactions to Portuguese gum rosin in a second group of 12 patients with gum rosin allergy was summarized as follows: 0.001% gum rosin (0 to 1 patient), 0.01% gum rosin (2 to 3 patients), 0.1% gum rosin (8 patients), 1% gum rosin (12 patients), and 10% gum rosin (1 0 to 12 patients). These data were based on patch tests with serial dilutions of Portuguese gum rosin in petrolatum.

The esterification of rosin with glycerol, in effect, reduced the allergenicity of rosin in dermatitis patients. Five of eight patients had positive reactions to 10% tall oil rosin in petrolatum, whereas four of eight patients had positive reactions to 20% glycerolesterified tall oil rosin in petrolatum. Additionally, seven of eight patients had positive reactions to 5% Portuguese gum rosin in petrolatum and three of eight patients had positive reactions to 20% glycerol-esterified gum rosin in petrolatum.

Glyceryl-1-monoabietate was identified as a contact allergen in another study evaluating the allergenicity of rosin and its esterification products. Abietic acid (esterified to form glyceryl-1-monoabietate) is a main component of rosin, and, furthermore, clinical data indicate that it is easily oxidized to form contact allergens (e.g., 15~hydroperoxyabietic acid and its methyl ester). It is also important to note that oxidation products of abietic acid and dehydroabietic acid (also a main component of

ro.sin) that can be formed during storage have been found to be allergenic.

FDA concluded that the use of rosin as a substratum in color additive lakes is safe up to rosinated color additive concentrations of 9.0% in cosmetic products. This conclusion was based on the observation that no skin sensitization or photoallergic reactions to cosmetic formulations containing rosinated, color additives at concentrations up to 9.0% were noted in human subjects. The human data, submitted by CTFA, included a photoallergy test using 312 subjects and a composite of repeat-insult patch tests on a total of 2381 subjects.

Information from the earlier safety assessment of Arachidonic Acid is considered relevant, in that the concems raised therein also apply to the safety assessment of Glyceryl Arachidonate. The CIR Expert Panel had concluded that the safety of Arachidonic Acid had not been documented and substantiated for cosmetic product use. Additional safety data that are needed include

I. Dermal absorption data

Based on the results of the absorption studies, the Panel indicated that there may be a need for the following data:

2. Immunomodulatory data 3. Carcinogenicity and photocarcinogenicity data 4. Human irritation, sensitization, and photosensitization data.

DISCUSSION A primary concern regarding the safety of Glyceryl Man

esters is the possible presence of Glyceryl Diesters, and, specifically, the 1 ,2 diesters, which are known to have adverse effects. After reviewing impurities data on 14 Glyceryl Monoesters (90% pure), the Panel concluded that the level of 1,2-diacylglycerols ( 1 ,2 (mono )glycerol diester) in Glyceryl Monoesters is not sufficient to wan·ant any concern about effects on signal transduction and resulting effects on cell growth and proliferation that are associated with 1 ,2-diacylglycerol-induced activation of protein kinase C (PKC). The results of the impurities analysis indicated that only one of the 14 Glyceryl Monoesters, Glyceryl Palmitate/Stearate, contained (mono)glycerol diester.

Of approximately 4% of the (mono )glycerol diester content of Glyceryl Palmitate/Stearate, 29% is actually the 1 ,2 (mono )glycerol diester. Thus, the concentration of 1,2 (mono)glycerol diester in Glyceryl Palmitate/Stearate is approximately 1.2%. In addition, the Panel noted the absence of tumor promotion activity in a study using Glyceryl Stearate. The Panel noted that if 1.2% represents the maximum concentration of this impurity in cosmetic grade Glyceryl Monoester, then the concentration of 1 ,2-diacylglycerol in cosmetics would be significantly less, considering that current use concentration data from the cosmetics industry indicate that product concentrations of Glyceryl Monoesters range from 0.1% to 12%.

Given that Glyceryl La urate is known to enhance the skin penetration of other chemicals, but that data are not available on the



penetration enhancement activity of o.ther Glyceryl Monoesters, the Panel agreed that the manufacturers should consider the skin penetration enhancement potential ~fall Glyceryl Monoesters when formulating cosmetic products to ensure safety.

The Expert Panel pi·eviously .stated that the available inhalation toxicity data are insufficient for addressing the Panel's concem over the use of Glyceryl Monoesters in aerosolized products, which relates to the potential surfactant activity of these ingredients on the lungs. After further review of this issue, focusing primarily on the use of Glyceryl Caprylate/Caprate in hair sprays, the Panel determined that Glyceryl Caprylate/Caprate can be used safely in these products, ·because the ingredient particle size is not respirable. The Panel reasoned that the particle size of anhydrous hair sprays (60 to 80 J.lm) and pump hair sprays (>80 J.lm) was large compared to the median aerodynamic diameter of 4.25 ± 1.5 J.lm for a respirable particulate mass.

Though mammalian genotoxicity data on the Glyceryl Monoesters were not available, the Panel concluded that they are not likely genotoxic agents based on the chemical structures of these compounds and negative Ames test data. Limited carcinogenicity data were negative, and data on the Glyceryl Monoester, Glyceryl Stearate indicated that 5% Glyceryl Stearate in acetone was not a tumor promoter in Swiss mice. These data, combined with the observation that maximum use concentrations of Glyceryl Monoesters associated with most (but not all) of the product type categories for cosmetics are _::5%, led the Panel to discount any carcinogenic risk.

The Panel expressed specific concerns relating to the safety of Glyceryl Rosinate, Glyceryl Hydrogenated Rosinate, Glyceryl Collagenate, and Glyceryl Arachidonate in cosmetics, based on the specific chemical with which glycerin is esterified.

Glyceryl Rosinate is defined as the monoester of glycerin and mixed long-chain acids derived from rosin, and Glyceryl Hydrogenated Rosinate is defined as the monoester of glycerin and hydrogenated mixed long-chain acids derived from rosin. The Panel recognizes the potential for contamination of cosmetic grade samples of Glyceryl Rosinate and Glyceryl Hydrogenated Rosinate with rosin, a moderate sensitizer. The Panel also noted that abietic acid, the main component of rosin, is easily oxidized to form contact allergens such as 15-hydroperoxyabietic acid and its methyl ester; glyceryl-1-monoabietic acid. Moderating this concem are data indicating that the sensitization potential of rosin is reduced by esterification with glycerol.

The Panel determined that this concem could be adequately addressed by establishing a concentration limit for Glyceryl Rosinate in cosmetic products that is based on the highest test concentration in human skin sensitization studies that did not induce sensitization. Skin irritation and sensitization were observed in 1 of 49 subjects patch tested (semiocclusive patches) with a trade mixture containing 10% Glyceryl Rosinate. In the other human study, neither skin irritation nor sensitization was observed in any of the 51 subjects patch tested (semiocclusive patches) with a trade mixture containing 10% Glyceryl Hydro-

genated Rosinate. After reviewing these negative data and considering that the highest reported use concentrations of Glyceryl Rosinate at 10% in an eyebrow pencil and up to 12% in a mascara (products applied to the eyebrows or eyelashes), the Panel agreed that Glyceryl Rosin ate and Glyceryl Hydrogenated Rosinate could be considered safe as used in cosmetic products. The Panel reasoned that any sensitization potential associated with Glyceryl Rosinate or Glyceryl Hydrogenated Rosinate at a concentration of 10% or 12% in a semi occlusive patch test would be significantly reduced in cosmetic products in which the mode of application results in minimal contact with the skin and does not involve any form of occlusion.

After reviewing the positive skin irritation study (rabbits, occlusive patches) on an undiluted trade mixture containing 50% Glyccryl Rosinate and 50% octyldodecyl myristate, the Panel agreed that the irritation potential of this material would be significantly reduced under the conditions of cosmetic use (i.e., dilution to current use concentrations of Glyceryl Rosinate and absence of occlusion). .

The Panel noted that the photosensitization potential ofGlyceryl Monocsters in cosmetics is not an issue, based on the negative UV absorption data on 14 ingredients and human photoallergenicity data on a cosmetic product containing 1% Glyceryl Rosinate that were provided.

Because protein found in cartilage and other connective tissues in animals is the source of collagen, the Expert Panel stipulates that Glyceryl Collagenate should be free of infectious agents.

The CIR Expert Panel has issued a Final Report with an insufficient data conclusion on Arachidonic Acid. Because it is likely that Glyceryl Arachidonate will be hydrolyzed to Arachidonic Acid, the Panel noted that the data needed for completion of the safety assessment on Arachidonic Acid are also applicable to Glyceryl Arachidonate. Dermal absorption data are needed. Based on the results of the absorption studies, the Panel indicated that there may be a need for the following data: immunomodulatory data; carcinogenicity and photocarcinogenicity data; and human irritation, sensitization, and photosensitization data.

CONCLUSIONS Based on the available animal and clinical data included in

this report, the CIR Expert Panel concludes that the following Glyceryl Monoesters are safe as cosmetic ingredients in the present practices of use and concentration: Glyceryl Laurate, Glyceryl Laurate SE, Glyceryl Laurate/Oleate, Glyceryl Adipate, Glyceryl Alginate, Glyceryl Arachidate, Glyceryl Behenate, Glyceryl Caprate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Citrate/Lactate/Linoleate/Oleate, Glyceryl Cocoate, Glyceryl Collagenate, Glyceryl Erucate, Glyceryl Hydrogenated Rosinate, Glyceryl Hydrogenated Soyate, Glyceryl Hydroxystearate, Glyceryl Isopalmitate, Glyceryl Isostearate, Glyceryl Isostearate/Myristate, Glyceryl Isostearates, Glyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Montanate, Glyceryl Myristate, Glyceryl



Isotridecanoate/Stearate/Adipate, <;Jlyceryl Oleate SE, Glyceryl Oleate/Elaidate, Glyceryl Palmitate, Glyceryl Palmitate/ Stearate, Glyceryl Palmitoleate, Gyceryl Pentadecanoate, Glyceryl Polyacrylate, Glyceryl Rosinate, Glyceryl Sesquioleate, Glyceryl/Sorbitol Oleate/Hy~roxystearate, Glyceryl Stearate/ Acetate, Glyceryl Stearate/Maleate, Glyceryl Tallowate, Glyceryl Thiopropionate, and Glyceryl Undecylenate.

The Panel also concludes that the available data are insufficient to support the safety of Glyceryl Arachidonate in cosmetic formulations.

REFERENCES American Conference of Governmental Industrial Hygienists (ACGIH). 1991.

Threshold limit values for chemical substances and physical agents in the workroom environment with intended changes for 1990-1991. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

Andersen, F. A. I 993. Final report on the safety assessment of arachidonic acid. J. Am. Coli. Toxicol. 12(5):481-559.

Aungst, B. J., N.J. Rogers, and E. Shefter. 1986. Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amides. Int. J. Pharm. 33:225-234.

Biogir, S. A. Conseil Recherche. I 989. Assessment of cutaneous tolerance in the rabbit. Index of primary cutaneous irritation. Extol 2040 glycerol monoisostearate No. 82350. (English translation). Report No.JC 88.1516. Unpublished data submitted by CTFA, May II, 1999 (18 pages).2

Biosearch, Inc. I 992a. Irritation screening study. Pure Gloss 3402-35 (lipstick, as supplied) containing I% glyceryl rosin ate. Unpublished data submitted by

CTFA (14 pages).2

Biosearch, Inc. 1992b. Modified Draize repeated insult patch test study in human subjects. Pure Gloss 3402-35 (lipstick, as supplied) containing I% glyceryl rosinate. Unpublished data submitted by CTFA (II pages).2

Biosearch, Inc. J992c. Human phototoxicity test. Pure Gloss 3402-35 (lipstick, as supplied) containing I% glyceryl rosinate. Unpublished data submitted by CTFA (8 pages).2

Biosearch, Inc. 1992d. Human photoallergy study. Pure Gloss 3402-35 (lipstick, as supplied) containing I% glyceryl rosinate. Unpublished data submitted by CTFA (9 pages).2

Blobe, G. C., L. M. Obeid, andY. A. Han nun. I 994. Regulation of protein kinase C and role in cancer biology. Cancer Metastasis Rev. 13:411-431.

Bower, D. 1999. Unpublished information on hair spray particle sizes provided at the September 9, 1999 CIR Expert Panel meeting.2

Brooks Industries. 1998. Specification, material safety data sheet, and technical data on Glyceryl Collagenate. Unpublished data submitted by CTFA, May

21, 1999.2

Budavari, S. I 989. The Merck index. An encyclopedia of chemicals, drugs, and biologicals, 983-984, 1530-1531, 1534. Rahway, NJ Merck & Co., Inc.

Centre de Recherche et d'Elevage des Oncins. I 975. Tests de tolerance chez le lapin: Indice d'irritation primaire. Irritation oculaire. Unpublished data submitted by CTFA, March 10, 1999 (10 pages).2

Chaibi, A., L. H. Ababouch, and F. F. Busta. 1996a. Inhibition of bacterial spores and vegetative cells by glycerides. J. Food Protection59:?16-722.

Chaibi, A., L. H. Ababouch, and F. F. Busta. I 996b. Inhibition by monoglycerides of L-alanine-triggered Bacillus cereus. J. Food Protection 59:832-837.

Consumer Product Testing Company. 1990a. Acute oral toxicity in rats. P.E.G./M.O.D. Purified Ester Gum!M.O.D. (Lot No. 00207). Experiment reference number: 90231-1. Unpublished data submitted by CTFA, June 22, 2000 (2 pages).2

2Available for review from the Director, Cosmetic Ingredient Review, 1101

17th Street, NW, Suite 310, Washington, DC, 20036, USA.

Consumer Product Testing Company. 1990b. Primary ocular irritation in rabl:iits. P.E.G./M.O.D. Purified Ester Gum!M.O.D. (Lot No. 00207). Experiment reference number: 90231-1. Unpublished data submitted by CTFA, June 22, 2000 (5 pages).2

Consumer Product Testing Company. 1990c. Primary dermal irritation in rabbits. P.E.G./M.O.D. Purified Ester Gum!M.O.D. (Lot No. 00207). Experiment reference number: 9023 I -1: Unpublished data submitted by CTFA, June 22, 2000 (7 pages).2

Consumer Product Testing Company. I 990d. Comedogenicity assay in rltbbits. P.E.G./M.O.D. Purified ester gum!M.O.D. (Lot No. 00207). Experiment reference number: 90231-2. Unpublished data submitted by CTFA, June 22, 2000 (I 0 pages).2

Consumer Product Testing Company. 1997. Repeated insult patch test (protocol no. 1.01 ). PEGMODWP-20 Lot #7045JWOI. Unpublished data submitted by CTFA, June 22, 2000 (8 pages).2

Consumer Product Testing Company. 2000. Repeated insult patch test (protocol no. I .01 ). Hydrogenated PEG/MOD (20) (Lot #00 124 ). Experiment reference number: C00-0171.01 (9 pages).2 Unpublished data submitted by CTFA June 2000.

Cosmetic, Toiletry, and Fragrance Association (CTFA). I 975. Guinea pig skin sensitization test no. 75.213. Laurinic monoglyceride. Unpublished data submitted by CTFA, May II, 1999.2

CTFA. I 985. Skin sensitization study (test reference SSM85288). Glyceryl isostearate. Unpublished data submitted by CTFA, May I I, I 999.2

CTFA. 1999. Ingredient use survey-use concentration data. Unpublished data submitted by CTFA, July 26, 1999 (4 pages).2

Cosmo Trends. no date. Cosmo Trends specialties series. Purified ester gum!M.O.D. = PEGMOD. Unpublished data submitted by CTFA, June 22, 2000 (5 pages).2

Danisco Ingredients. I 996. A modified Draize repeat insult patch test in healthy volunteers to investigate the irritation and sensitization potential of nine cosmetic ingredients of edible quality and a control (liquid paraffin) following repeated cutaneous patch applications (Report No. DANFOO I). Unpublished data submitted by Danisco Ingredients. February, 1999 (70 pages).2

Danisco Ingredients. 1999a. Calculation of the octanol/water partition coefficients. Unpublished data submitted by CTFA, July 15, 1999 (3 pages).2

Danisco Ingredients. 1999b. Inhalation toxicity data. Unpublished data submitted by CTFA, July 15, 1999 (I page).2

Danisco Ingredients. I 999c. Impurity analysis for glycerol monoesters. Unpublished data submitted by CTFA, August 25, 1999 (20 pages).2

Danisco Ingredients. 1999d. "Impurity analysis" for glycerol monoesters. Unpublished data submitted by CTFA, September 9, 1999 (2 pages).2

Danisco Ingredients. J999e. UV-spectra for glycerol monoesters. Unpublished data submitted by CTFA, August 30, 1999 (18 pages).2

Danisco Ingredients. I 999f. A modified Draize repeat insult patch test in healthy volunteers to investigate the irritation and sensitization potential of nine cosmetic ingredients of edible quality and a control (liquid paraffin) following repeated cutaneous patch applications. Unpublished data submitted by CTFA, July 22, 1999 (I 08 pages).2

Eagle, E., and C. E. Poling. 1955. The oral toxicity and pathology of polyoxyethylene derivatives in rats and hamsters. Food Res. 2 I :348-361.

Elder, R. L., ed. 1982. Final report on the safety assessment of glyceryl stearate and glyceryl stearate/SE. J. Am. Col!. Toxicol. 1:169-192.

Elder, R. L., ed. I 986. Final report on the safety assessment of glyceryl oleate. J. Am. Col!. Toxicol. 5:391-413.

European Economic Community (EEC). 2001. EEC Cosmetics Directive 761768/EEC, as amended, Annexes /through VII. Brussels: EEC.

Fitzhugh, 0. G., P. J. Schouboe, and N. A. Nelson. 1960. Oral toxicities of lauric acid and certain lauric acid derivatives. Toxicol. Appl. Pharmacal. 2:59-67.

Food and Drug Administration (FDA). 1988. Memorandum dated June 27, 1998. Color additive petition no. ?TO 130. Safety evaluation of substrata and precipitants used in the manufacture of color additive lakes. Washington, DC: FDA.



FDA. J994a. Memorandum dated July 13, 1994. Safety evaluation of rosin in color additive lakes. Washington, DC: FDA.

FDA. J994b. Memorandum dated August 22, 1994. Safety evaluation of dermal sensitization and photosensitization of rosinated lakes of D&C Red No. 6, D&C Red No.7, and D&C Red No. 34. Washington, DC: FDA.

FDA. 1998. Frequency of use of cosmetic ingredients. FDA database. Washington, DC: FDA.

Fregert, S. 1981. Manual of contact dermatitis, 2nd ed., 71-81. Copenhagen:

Munksgaard. Giifvert, E., L. P. Shao, A.-T. Karlberg, U. Nilsson, and J. L. G. Nilsson. 1994.

Allergenicity of rosin (colophony) esters. II. Glyceryl monoabietate identified as contact allergen. Contact Dermatitis 28:229-234.

Gattefosse, S. A. 1998. Data sheet. Peceol isostearique (Glyceryl Isostearate). Unpublished data submitted by CTFA, March 10, 1999 (2 pages).2

Gattefosse, S. A. 1999. Material safety data sheet according to 911155 EC. Unpublished data submitted by CTFA, March 10, 1999 (4 pages)2

Gerrard, J. M., and G. Graff. 1980. 1-Arachidonyl-monoglyceride causes platelet aggregation: Indirect evidence for an acylglycerol acylhydrolase involvement in the release of arachidonic acid for prostaglandin synthesis. Prostaglandins

Med. 4:419-430. Giron, D., R. Link, and S. Bouissel. 1992. Analysis of mono-, di- and triglyc

erides in pharmaceutical excipients by capillary supercritical fluid chromatography. J. Pharm. Biomed. Anal. 10:821-830.

Hayakawa, R., K. Matsunaga, M. Suzuki, Y. Arima, andY. Ohkido. 1987. Lipstick dermatitis due to C 18 aliphatic compounds. Contact Dermatitis 16:215-

219. Henkel KgaA. 1994. Monomuls® 90-LJ2 (Glyceryl Laurate) Toxicological

Evaluation. Unpublished data submitted by CTFA, January 27, 1999 (4

pages).2

Henkel KgaA. 1996. Monomuls® 90-LI2 (Glyceryl Laurate). Quality control and product descriptive data. Unpublished data submitted by CTFA, January

27, 1999 (2 pages).2

Holland, K. T., D. Taylor, and A.M. Farrell. 1994. The effect of glycerol monolaurate on growth of, and production of toxic shock syndrome toxin-] and lipase by, Staphylococcus au reus. J. Antimicrob. Chemother. 33:41-55.

Huckle, W. R., and H. S. Earp. 1994. Regulation of cell proliferation and growth by angiotensin II. Pro g. Growth Factor Res. 5:177-194.

Hills, A. G. 1996a. Priifung der akuten oraien toxicitiit von Imwitor 375 an der ratte (Testing of the acute oral toxicity of Imwitor 375 [Glyceryl Citrate!Lactate/Linoleate/Oleate] on rats) (English translation) (Final Report No. A0-96/0182). Unpublished data submitted by CTFA, May 5, 1999 (3 pages).2

Hills, A. G. J996b. Priifung der akuten dermalen toxizitiit von lmwitor 375 an der ratte (Testing of the acute dermal toxicity oflmwitor 375 on rats) (English translation) (Final Report No. AD-96/0182). Unpublished data submitted by CTFA, May 5, 1999 (3 pages). 2

Hiils, A. G. 1996c. Priifung auf akute augen- und schleimhautreizung von Imwitor 375 am kaninchen (Testing for acute eye and mucous membrane irritation of lmwitor 375 on rabbits) (English translation) (Final Report No. AA-96/0182). Unpublished data submitted by CTFA, May 5, 1999 (3 pages)2

Hiils, A. G. 1996d. Priifung auf akute hautreizwirkung von Imwitor 375 am kaninchen (Testing of the acute skin irritation effect of Imwitor 375 on rabbits) (English translation (Final Report No. AH-96/0182)). Unpublished data submitted by CTFA, May 5, 1999 (3 pages).2

Hiils, A. G. 1996e. Priifung auf akute augen- und schleimhautreizung von Imwitor 375 am kaninchen (Testing for sensitization of the skin of Imwitor 375 on guinea pigs [Buehler method]) (Final Report No. HS-96-0182). Unpublished data submitted by CTFA, May 5, 1999 (3 pages).2

Hills, A. G. 1996f. S. typhimurium reverse mutation assay (Ames Test) (Final Report No. AM-96/9). Unpublished data submitted by CTFA, May 5, 1999

(25 pages).2

Hills America, Inc. no date. Product information on glyceryl citrate!lactatellinoleate/oleate, glyceryl stearate citrate, glyceryl cocoate, and glyceryl caprylate. Unpublished data submitted by CTFA (15 pages).2

Informatics, Inc. 1973. GRAS (Generally Recognized as Safe) Food Ingredients-Glycerine and Glycerides. NTIS Report No. PB-221 227.

lnstitut Frans;ais de Recherches et Essais Biologiques [IFREB]. 1977. lndice d'irritation oculaire chez le lapin. Indice d'irritation primaire cutanee chez le lapin. Unpublished data submitted by CTFA, March 10, 1999 (22 pages).2

International Research Services, Inc. 1995. A study to assess the skin sensitization potential of four ( 4) test products when applied topically to the skin of healthy humans in a shared panel assay (IRS11241 1294PSL). Unpublished data submitted by CTFA (II pages).2

Ivy Laboratories. 1990. The determination of the contact-sensitizing potential of four materials by means of the maximization test. Lip gloss 90033-0 I containing 2.0% glyceryl rosinate RI9149. Unpublished data submitted by CTFA (12 pages).2

Ivy Laboratories. 1996. The determination of the contact-sensitizing potential of four materials by means of the maximization assay. Foundation 06636-11 containing 4.0% glyceryl rosinate (RI2326). Unpublished data submitted by CTFA (10 pages).2

Jensen, P. A., and D. O'Brien. 1993.lndustrial hygiene. In Aerosol measurement. Principles techniques and applications, eds. K. Willeke and P. A. Baron, 538-540. New York: John Wiley and Sons, Inc.

Kabara, J. J. 1984. Cosmetic and drug preservation. Principles and practice, 305-322,618,740. New York: Marcel Dekker.

Kabara, J. J., M. Ohkawa, T. Ikekawa, T. Katori, and N. Nishikawa. 1985. Examinations on antitumor, immunological, and plant-growth inhibitory effects of mono glycerides of caprylic, capric, and lauric acids and related compounds. Pharmacal. Ejf. Lipids 13:263-272.

Karl berg, A. 1988. Contact allergy to colophony. (VII). Sensitizing studies with oxidation products of abietic and related acids. Acta Derma to-Venereal. Suppl. 139:1-46.

Kato, A., K. Ando, S. Suzuki, G. Tamura, and K. Arima. 1969. Antitumor activity of monoglycerides and other esters of fatty acids. J. Antibiot. 22:83-84.

Kato, A., K. Ando, G. Tamura, and K. Arima. 1971. Effects of some fatty acid esters on the viability and transplantability of Ehrlich ascites tumor cells. Cancer Res. 31 :501-504.

Kimber, 1., G. F. Gerberick, and D. A. Basketter. 1999. Thresholds in contact sensitization: Theoretical and practical considerations. Food Chem. Toxicol. 37:553-560.

Lee, M. W., and D. L. Severson. 1994. Signal transduction in vascular smooth muscle: Diacylglycerol second messengers and PKC action. Am. J. Physiol. 267:C659-C678.

Leo, A., C. Hansch, and D. Elkins. 1971. Partition coefficients and their uses. Chemical Rev. 71 :525-616.

Levy, L., V. Alvaro, C. Dubray, and D. Joubert. 1994. Ca(2+ )-dependent protein kinase C isoforms in rat pituitary hyperplasia: effect of in vivo treatment with quinagolide. Eur. J. Pharmacal. 16:327-334.

Lewis, R. J., ed. 1993. Hawley's condensed chemical dictionary, 12th ed., 568,1088,1180. New York: Van Nostrand Reinhold.

Lide, D. R., and H. P. R. Frederikse, eds. 1993. CRC handbook of chemistry and physics. A ready reference book of chemical and physical data, 74th ed., 3-260-3-261,3-502-3-504. Boca Raton: CRC Press.

Lyman, W. J., W. F. Reehl, and D. H. Rosenblatt. 1982. Handbook of chemical property estimation methods. New York: McGraw-Hill.

Maruyama, K., and C. Yonese. 1986. Separation and quantitative determination of monoacylglyceryol mixtures by reversed phase HPLC. J. Am. Oil Chem. Soc. 63:902-905.

Mattson, F. H., and R. A. Volpenhein. 1964. The digestion and absorption of triglycerides. J. Bioi. Chem. 239:2772-2777.

McEwen, G. N., Jr. 2000. Memorandum on glyceryl rosinate and glyceryl hydrogenated rosinate to Dr. F. Alan Andersen, dated June 22, 2000.2

National Academy of Sciences (NAS). 1960. The safety of mono- and diglycerides for use as intentional additives in food (NAS publication no. 251 ). Washington, DC: NAS.

Niederpruem, H., H. Schweikert, J. W. Thueroff, and K. S. Zaenker. 1995. Inhibition of steroid 5 alpha-reductase activity by aliphatic fatty acids. Candidates for chemoprevention of prostate cancer. Ann. N. Y. Acad. Sci. 768:227-230.



Nomura, H., A. Katsuhiko, K. Sekiguchi, U. Kikkawa, andY. Nishizuka. 1986. Biochem. Biophys. Res. Commun. 140:'1143-1151.

Oh, D.-H., and D. L. Marshall. 1996. Mono Iaurin and acetic acid inactivation of Listeria monocytogenes attached to stainless steel. J. Food Protection 59:249-252.

Okumura, M., Y. Naka\nori, Y. Ysshida, H. Niwa, andY. Sugibayashi. 1990. Effect of monoglycerides on the percutaneous absorption of papaverine hydrochloride. Drug Des. Delivery 6:137-148.

Pepe, R. C., J. A. Wenninger, and G. N. McEwen, Jr., eds. 2002. International cosmetic ingredient dictionary and handbook, 9th ed. Washington, DC: CTFA.

Petschow, B. W., R. P. Batema, and L. L. Ford. 1996. Susceptibility of Helicobacter pylori to bactericidal properties of medium-chain monoglycerides and free fatty acids. Ant(microb. Agents Chemother. 40:302-306.

Procter & Gamble Company. 1950. The comparative nutritive value of certain mono-, di-, and triglycerides. Submitted by FDA in response to an FOI request, 1998 (41 pages). 2

Projan, S. J., S. Brown-Skrobot, P. M. Schlievert, G. Vandenesch, and R. P. Novick. 1994. Glycerol monolaurate inhibits the production of betalactamase, toxic shock toxin-!, and other staphylococcal exoproteins by interfering with signal transduction. J. Bacterial. 176:204-209.

Rempe, J. M., and L. G. Santucci. 1997. CTFA list of Japanese cosmetic ingredients, 3rd ed. Washington, DC: CTFA. ,

Sanchez-Piiiera, P., V. Micol, C. Corbalan-Garcia, and J. C. G6mez-Fernandez. 1999. A comparative study of the activation of protein kinase C et by different diacylglycerol isomers. Biochem. J. 337:387-395.

Saffiotti, U., and P. Shubik. 1963. Studies on promoting action in skin carcinogenesis. Nat!. Cancer Ins/. Monogr. 10:489-507.

Schlievert, P.M., J. R. Deringer, M. H. Kim, S. J. Projan, and R. P. Novick. 1992. Effect of glycerol monolaurate on bacterial growth and toxin production. Amimicrob. Agents Chemother. 36:626-631.

Scientific & Technical Information Network (STN) International. 1997. Properties of esters of glycerin and lauric acid. Registry database file. Columbus, OH: STN International.

Shao, L. P., E. Glifvert, A.-T: Karlberg, U. Nilsson, and J. L. G. Nillson. 1993. The allergenicity of glycerol esters and other esters of rosin (colophony). Contact Dermatitis 31:11-17.

Shin-Ei Chemical Company, Ltd. 1998. Material safety data sheet on glyceryl rosinate, octyldecyl myristate. Unpublished data submitted by CTFA, June 27, 2000 (3 pages).2

Takano, S., andY. Kohdoh. 1987. Monoglyceride analysis with reversed phase HPLC. J. Am. Oil. Chem. Soc. 64:1001-1003.

Tanaka, M., S. Shimizu, and S. Miyakawa. 1993. Contact dermatitis from glyceryl di-isostearate. Contact Dermatitis 29:41-42.

Unichema International. 1997a. Isostearate esters of glycerol and polyglycerol: Safety evaluation. Unpublished data submitted by CTFA, May 4, 1998 (8 pages).2

Unichema International. 1997b. Glyceryl monoesters of fatty acids: Safety evaluation. Unpublished data submitted by CTFA, May 4, 1998 (12 pages).2

US Cosmetics Corporation. no date. A new product for cosmetics. Purified ester gum-2-octyldodecyl myristate (Purified Ester GurniM.O.D). Unpublished data submitted by CTFA, June 22, 2000 (4 pages)OZ

US Cosmetics Corporation. 1998. PEG/MOD (Purified Ester Gum/M.O.D.). Unpublished data submitted by CTFA, June 22, 2000 (9 pages).2

Witcher, K. J., R. P. Novick, and P.M. Schlievert. 1996. Modulation of immune cell proliferation by glycerol monolaurate. Clin. Diagn. Lab. Immunol. 3:10-13.



2

Final Report on the Safety Assessment of Glyceryl Ricinoleate

Glyceryl Ricinoleate is the monoester of glycerol and ricinoleic acid. Castor oil contains 87-90% Glycerol Ricinoleate. Ricinoleic acid is metabolized by both 13-oxidation and a-oxidation.

Acute oral toxicity tests in mice indicated that Glyceryl Ricinoleate has an LD50 greater than 25.0 mljkg and is, at most, mildly irritating to unrinsed rabbit eyes. This ingredient was not a primary skin irritant.

Castor oil was nonmutagenic by the Ames test. Ricinoleic acid was not a carcinogen when tested in mice.

In human single-insult occlusive patch tests, no indication of skin irritation potential was observed in the two products containing 5.6% Glyceryl Ricinoleate.

The available data on Glyceryl Ricinoleate were insufficient to determine whether this ingredient, under each relevant condition of use, was either safe or not safe. The types of data required before a decision can be made include: (1) 28 day chronic dermal toxicity in guinea pigs, and (2) clinical sensitization and photosensitization studies (or an appropriate ultraviolet spectrum instead of the photosensitization data).

INTRODUCTION

T he following report documents all the relevant published and unpublished data available to the Cosmetic Ingredient Review (CIR) on Glyceryl

Ricinoleate. The CIR Expert Panel reviewed these data and concluded that additional information is required to substantiate the safety of Glyceryl Ricinoleate for use in cosmetic products. The types of data needed to assess the safety of this cosmetic ingredient are outlined in the Discussion sectio.n of this report.

CHEMISTRY

Glyceryl Ricinoleate is a monoglyceride obtained from the glycerolysis of castor oil.

721



Glyceryl Ricinoleate (CAS No. 141-08-2; 1323-38-2) is a monoester of glycerol and the fatty acid, ricinoleic acid or 12-hydroxy-cis-9-octadecenoic acid. The ricinoleic acid moiety is esterified to the a-carbon of glycerol.(1)

0 H H II I I

H -C-0-C-(CH ) -C=C-CH -CH-(CH ) -CH 2 I 27 2 I 2s 3

HO-C-H OH I

H 2-C-OH

Glyceryl Ricinoleate

Glyceryl Ricinoleate is a light yellow, oily liquid that has a characteristic odor. It is dispersible in water, slightly soluble in methanol, soluble in ethanol, ether, acetone, benzene, cottonseed oil, and ethyl acetate, and insoluble in mineral oil and aliphatic hydrocarbonsY- 4l Glyceryl Ricinoleate is also known as a-monoricinolein, glyceryl or glycerol 1-monoricinoleate, or 1-mono-12-hydroxy-cis-9-octadecenoate. (l,3J

The molecular weight of Glyceryl Ricinoleate is 372.55. Its density is 1.028 (20/4°C), and its boiling point has not been reported.<2,3,SJ Specifications for its cosmetic use include a minimum pour point of 35°F, a maximum acid value of 8.0, an iodine value between 70 and 90, and a saponification value between 160 and 170.

Analytical Methods

Methods for the analysis of Glyceryl Ricinoleate include gas chromatography of methyl ricinoleate derivatives, (G-SJ nuclear magnetic resonance spectrometry,<9·10l high-performance liquid chromatography,<11 l and infrared spectrometry.<6l A chemical test for glycerol or its 1-monoglycerides involves periodate or lead tetra-acetate oxidation of primary alcohol groups and colorimetric quaritization.<6•12l

Reactivity

Reactions of Glyceryl Ricinoleate are primarily those of glycerol and ricinoleic acid and the glyceryl ester. Typical reactions include esterification, saponification, reduction and oxidation, hydrogenation, amide formation, epoxidation, halogenation, and dehydration.<13•14l

Method of Manufacture and Impurities

Monoglycerides occur naturally in fats and oils that have become partially hydrolyzed.<5•15l They are manufactured by reacting fatty acids or raw or hydrogenated fats and oils with an excess of glycerol or polyglycerols. The latter method, a glycerolysis reaction, depending on the molar ratios of the


ASSESSMENT: GLYCERYL RICINOLEATE 723

reactants, can yield product mixtures containing varying amounts of monoglycerides.

Commercial glycerides, except preparations that have been fractionated, are usually mixtures of mono-and diglycerides and small quantities of triglycerides. These preparations may also contain free fatty acids and glycerol. cs) Several grades of monoglycerides are available for different uses. A label of "40% monos" or "60% monos" refers to the monoglyceride content of the preparation.c1s) A higher monoglyceride content is usually obtained by fractional distillation.

The reported monoglyceride content includes both a- and /3-monoglycerides and may also include glyceryl monoesters of other fatty acids, depending on the original fat or oil source used in the manufacturing process. The a-monoglyceride isomer predominates in these preparations: the /3-monoglyceride readily isomerizes to form the a-monoglyceride.c1s)

The commercial manufacture of Glyceryl Ricinoleate involves an alkalicatalyzed glycerolysis of castor oil, followed by distillation to concentrate the monoglyceride. Another method involves refluxing of reactants in a mutual solvent, such as phenol or pyridine and approximately 2.5% sodium bicarbonate. High-purity Glyceryl Ricinoleate can be synthesized by the reaction of isopropylidene glycerol (a product of the condensation of glycerol and acetone) with methyl ricinoleate in the presence of a sodium methoxide catalyst. The methyl ricinoleate is made by alkali-catalyzed methanolysis of castor oii.C1 3)

Castor oil, obtained from the seeds of the castor plant, Ricinus communis L., Euphorbiaceae, is composed of triglycerides of fatty acids, 87% to over 90% of which is ricinoleic acid.C8•16•17) The quantity of ricinoleic acid may range from 84 to 90% of the fatty acid content in different castor bean varieties.C18)

Other fatty acids include oleic (7%), linoleic (3%), palmitic (2%), stearic (1%), and dihydroxystearic (trace) acids.

The cosmetic ingredient description of Glyceryl Ricinoleate did not contain data on the content or the quality of the Glyceryl Ricinoleate used by the cosmetic industry.(2)

COSMETIC USE

Glyceryl Ricinoleate was contained in 34 cosmetic formulations voluntarily reported in 1986 to the Food and Drug Administration by the cosmetic industry.C19) Reported concentrations of Glyceryl Ricinoleate in these makeup preparations, primarily eye shadows, eyeliners, and lipsticks, ranged from 0.1 to 50% (Table 1). In lipsticks Glyceryl Ricinoleate is used as a base ingredient, and in eye shadows it is used as a pigment binder.C20)

Voluntary filing of product formulation data with the U.S. Food and Drug Administration (FDA) by cosmetic manufacturers and formulators conforms to the tabular format listing preset ingredient concentration ranges and product categories in accordance with Title 21 Section 720.4 of the Code of Federal Regulations.C21 ) Since certain cosmetic ingredients are supplied by the manufacturer at less than 100% concentration, the value reported by the cosmetic



formulator may not necessarily reflect the actual concentration found in the finished product; the actual concentration is a fraction of that reported to the FDA. Data submitted within the framework of preset concentration ranges provide the opportunity for overestimation of the actual concentration of an ingredient in a particular product. An entry at the lowest end of a concentration range is considered the same as one entered at the highest end of that range, thus introducing the possibility of a 2- to 10-fold error in the assumed ingredient concentration.

Cosmetic products containing Glyceryl Ricinoleate may be applied to all areas of the skin, including mucous membranes. They are frequently applied to the face and may contact the eyes. Lipstick products may be ingested. Products containing Glyceryl Ricinoleate may be applied up to several times per day and may remain in contact with the skin for as long as 8-12 h.

NONCOSMETIC USE

Monoglycerides of edible fats or oils are generally recognized as safe (GRAS) as emusifying agents (21 CFR 182.4505)<21) and as substances migrating to foods from paper and paperboard products (21 CRF 182.90)<21 )

Monoglycerides can be indirect food additives as components of adhesives (21 CFR 175.105)<21 ) and as components of defoaming agents in paper and paperboard manufacturing (21 CFR 176.210).<21 )

Glyceryl Ricinoleate is listed as an allowable component of paper and paperboard contacting aqueous and fatty foods (21 CFR 176.170). <21 ) Glycerol ester mixtures of ricinoleic acid containing no more than 50% Glyceryl Ricinoleate can be used as antifogging agents and concentrations not exceeding 1.5% (w jw) of permitted plasticized vinyl chloride polymer concentrations (21 CFR 178.3130). <21 )

Castor oil and Glyceryl Ricinoleate were included in the 1982 FDA list of inactive ingredients for approved prescription drug products.<22)

Castor oil is also used as an active ingredient in some over-the-counter (OTC) wart-remover drug products.<23) Ricinoleic acid is used in some OTC vaginal contraceptive drug products.<24)

Other therapeutic applications for castor oil have been reviewed.<25) Various cultures have historically used castor oil in the treatment of digestive disorders, bronchitis, and cardiovascular congestion and as an antirheumatic and antiseborrheic. It is also used as an ointment for eye irritation and as a vehicle for ophthalmic solutions.<26) ·

BIOLOGY

Absorption, Distribution, Metabolism, and Excretion

Absorption

Dietary monoglycerides like Glyceryl Ricinoleate are digested and absorbed as are triglycerides of the dietY7) Following emulsification in the small intenstine and hydrolysis of the ester bond, primarily by pancreatic lipase,<25)



the monoglyceride moieties are absorbed into the intestinal mucosa by passive diffusion.

The enzymatic hydrolysis of Glyceryl Ricinoleate by pancreatic lipase is very rapid and yields glycerol and ricinoleic acid.<28) The fate of glycerol, a product of Glyceryl Ricinoleate hydrolysis, in intermediary metabolic pathways is well documented.<28- 31 ) Following phosphorylation and oxidation, glycerol as dihydroxyacetone phosphate may be catabolized via the glycolytic pathway. Alternatively, glycerol may be re-esterified to fatty acids to form glycerides.

Since the glycerides of ricinoleic acid are major components of castor oil, data from studies of castor oil can be used to determine the properties of the absorption, metabolism, distribution, and excretion of ricinoleic acid.

Ricinoleic acid has been used as a marker for the detection of castor oil uptake in animals and humans. Following the intragastric administration of 1 ml of medicinal-grade castor oil, 24.2% ricinoleic acid was recovered in the chyle of four fed Sprague-Dawley rats and 6.8% was recovered in fasted rates.

In two Sprague-Dawley rates that received 0.2 and 0.6 ml castor oil via a cannula to the duodenum, the lower dose resulted in 18.1% ricinoleic acid in the chyle and 6.2% in the lipids of the small intenstine, whereas the higher dose resulted in 3.0% ricinoleic acid in the chyle and 3.1% in lipids of the small intestine.<32)

Methyl ricinoleate and glyceryl triricinoleate were hydrolyzed in vivo by rats administered 1 ml of these compounds by gavageY ) Maximum concentrations of 49.9 and 22.7% free ricinoleic acid from respective administrations of methyl ricinoleate and glyceryl triricinoleate were detected 24 h later. Maximum concentrations of ricinoleic acid incorporated into glycerides after 24 h ranged from 18 to 39%.

When castor oil was withdrawn from the diet of rats, the ricinoleic acid accumulated over 4 weeks disappeared linearly with time.<34) No ricinoleic acid could be detected in the feces of rats by 48 h.

In humans, the absorption of castor oil was inversely related to the administered dose.<28) Medicinal-grade castor oil (90% ricinoleic acid content) containing a trace amount of [1311]castor oil (- 6 J.tCi) was orally administered to human subjects at doses ranging from 4 to 61 g. At the 4 g dose, less than 1% of the radioactivity was found in fecal extracts of a treated subject, contrasted with 90% radioactivity in the fecel extracts of subjects given the 61 g dose. Most of the subjects receiving doses of 10 g or more excreted almost all the ingested radioactivity within the first 24 h following administration. The possibility that the addition of iodine to ricinoleic acid altered its pharmacology was noted. The intestinal absorption of castor oil and ricinoleic acid was inversely related to doseY8,34)

In a clinical study, the intestinal lumen of healthy human volunteers was perfused with 10 mM ricinoleic acid or oleic acid.<35) Oleic acid was absorbed twice as fast as ricinoleic acid ( 41.9 ± 7.3 versus 21.6 ± 2.6 J.tmoljm per 25 em, respectively).

Distribution

Monoenoic and saturated a-hydroxy fatty acids, primarily those ranging in lengths from 12 to 24 carbon atoms, have been isolated from several mam-


...... ~

TABLE 1. Product Formulation Data for Glyceryl Ricinoleate

Total no. of Total no. formulations containing No. of product formulations within each concentration range (%)

Product category in category ingredient >25-50 >10-25 >5-10 ~5 >1-5 ~1 >0.1-1

Eye makup preparations 1797 24 5 17 Hair-coloring preparations 85 1 Lipstick 1552 7 3 4 Skin-cleansing preparations 729 2 2

(cold creams, lotions, liquids, and pads)

-- -1986 Totals 34 5 20 4 2

~ 0 Ill Source: From Reference 19. s: .,., -1 ;:; z

"' ~ .,., 0 .,., z -1 ~

~ .,., ::;;:



malian tissues, including brain, spleen, lungs, kidneys, and sciatic nerve, rat skin, and bovine plasmaY6) The a-hydroxy fatty acids in mammalian brain tissue are components of cerebrosides, sulfatides, and a minor ganglioside.<37)

An enzymatic system that converts nonhydroxy long-chain (20-26°C) fatty acids to the corresponding a-hydroxy fatty acids, detected in the brain, was closely integrated with cerebroside synthesis and myelin formation. Small quantities of ricinoleic acid have been isolated from the plasma, kidneys, lungs, and skin samples of the rat.<36)

Feeding of ricinoleic acid, glyceryl triricinoleate (as castor oil), or methyl ricinoleate (for varying periods of time depending on the exact experiment conducted) to rats resulted in intestinal absorption, activation to form ricinoleoyl CoA,<32) and incorporation into triglycerides primarily of depot fat.<33.38)

Activation of ricinoleic acid by the mucosal thiokinase of the rat was less efficient than that of oleic acid. <32) There were no significant alterations in the general fatty acid composition of lymph lipids, except for the introduction of ricinoleic acid into triglycerides.<33)

No ricinoleic acid was found in the liver or brain of rats fed 20% castor oil diets.<32) Ricinoleic acid was not incorporated into phospholipids of the small intestine, liver, or muscle or into glycerides of the liver of rats fed castor oil.<38•39) The results of in vitro studies with epithelial microsomes of intestinal mucosa(32) and hepatic microsomes<40) of rats supported the in vivo findings of the preferential incorporation of ricinoleic acid into triglycerides rather than phospho! i pids.

Radioactivity from C25 1]castor oil and C25 1]hydrolyzed castor oil (primarily free C25 1]ricinoleic acid, but including C25 1]oleic and C25 1]1inoleic acids) was measured in the blood, heart, liver, and kidneys of Swiss Webster albino mice following intravenous administration. <41 ) Distinct patterns of uptake and release of radioactivity from the two iodinated preparations were observed in all tissues.

Metabolism

Ricinoleic acid can be a source of calories in some species of animals.<42•43)

After partial degradation of ricinoleic acid via ,8-oxidation yielding three molecules of acetyi-CoA (per molecule of ricinoleic acid), 6-hydroxy-cis-3,7-dodecenoyi-CoA would result. Further ,8-oxidation, requiring trans-a,,B unsaturation, cannot continue. Two hypotheses for further degradation of the dodecenoic acid are (1) isomerization of the cis-,B,y double bond to the trans-a,,B double bond and (2) hydration of the double bond followed by oxidation and cleavage.<44) The first pathway yields 6-hydroxy-trans-2,3-dodecenoyi-CoA, which can be further catabolized by ,8-oxidation to yield two more molecules of acetyl CoA and a-hydroxy-octanoyi-CoA. The second pathway yields a molecule of propionyi-CoA and 3-hydroxy-nonano~+CoA, which can be easily degraded by ,8-oxidation to three molecules of acetyi-CoA and one molecule of propionyi-CoA.

The- a-oxidation pathway involving the cleavage of one carbon unit as carbon dioxide from the carbonyl terminus of fatty acids has been demonstrated in young plant leaves, germinating peanuts, bacteria, and heptic mitochondria and microsomes of the brain of animals.<29•36A5- 47) Intermediates



of the pathway in Escherichia coli, in brain microsome cultures from animals, and in leaves of plants are 2-hydroxy fatty acids.<47- 49>

Ricinoleic, hydroxyhexadecenoic, hydroxytetradecenoic, and hydroxydodecenoic acids were isolated from the fat of rats fed ricinoleic acid or castor oi1.<50•51 > The hydroxymonoenoic acids of 12-, 14-, and 16-carbon lengths were similar to the metabolites of ricinoleic acid obtained from degradation by f. coli cultures, two of which were characterized as 8-D-( + )-hydroxy-cis-5-tetradecenoic <52> and 6-hydroxy-cis-3-dodecenoic acid. <53>

Excretion

Hydroxystearic acid was found in the feces of humans, rats, and dogs with steatorrhea. <54- 56>

Bacterial hydrogenation of ricinoleic acid in the intestinal lumen was proposed as the explanation for the finding of hydroxystearic acid in the feces of rats fed castor oil in the diet (20% w jw).<32> After synthesis by intestinal bacteria, the hydroxy acids in these systems were absorbed via the portal system and excreted in the bile in an enterohepatic circulation. The proposed reaction forming the hydroxy acids involved hydration of the double bond in unsaturated fatty acids rather than oxidation of saturated fatty acids. Several species of fecal bacteria were able to hydrate unsaturated long-chain fatty acids.<57>

After evaluation by absorption, metabolism, distribution, and toxicity of glycerol and mono- and diglycerides (from edible fats and oils), the select committee on GRAS substances found no evidence that indicated a hazard to the public from these compounds at reported concentrations of use.<27•58>

Cathartic Properties

The hydrolysis of castor oil and Glyceryl Ricinoleate releases ricinoleic acid, which is the pharmacologically active ingredient responsible for the strong cathartic properties of castor oi I. <59> Catharsis usually occurs 4-8 h following the administration of castor oil.<26>

Ricinoleic acid inhibited water and electrolyte absorption from the small and large intenstine of animals and humans.<35•60- 62> It depressed the contractile activity of intestinal circular smooth muscle.<63•64> A dose-dependent cytotoxicity for ricinoleic acid ranging from 0.1 to 2.0 mM was observed in vitro in epithelial cells from the small intestine of hamsters.<65> Furthermore, ricinoleic acid caused erosion of intestinal villi and disorganization of the microvillous surface detected by scanning electron microscopy, indicating the potential malabsorption of nutrients due to its long-term use.<66> The mechanisms of action of ricinoleic acid involved in catharsis have been studied.<25•34•67•68>

Several studies have been done to delineate the clinical effects of the use of ricinoleic acid as a laxative. Fluid secretion was increased and intraluminal cell loss was reported in the intestines of human subjects perfused with 5 and 10 ml ricinoleic acid.<35•69>

The advisory review panel on OTC laxative, antidiarrheal, emetic, and antiemetic drug products concluded that castor oil was safe and effective taken orally as a single dose.<70> The active ingredient, ricinoleic acid, is



thought to promote bowel movement by inducing the colonic secretion of water and electrolytes. The panel noted that there was "no experimental evidence to support the assumption that the laxative acts to increase peristalsis through a direct irritant effect on the intestinal mucosa." It was concluded that regular peroral use of castor oil may cause excessive loss of water, electrolytes, and unabsorbed nutrients, precluding its repeated administration.

The use of OTC laxatives like castor oil was associated with the development of a dependence on the laxatives to ensure regular bowel movement. (?l)

The frequent and prolonged use of irritant cathartics may, in turn, result in the development of a "cathartic colon," a poorly functioning large intestine, which radiologically and pathalogically resembles chronic ulcerative colitis.

ANIMAL TOXICOLOGY

Acute Oral Toxicity

Glyceryl Ricinoleate was evaluated for acute oral toxicity in mice. A preliminary range-finding study was performed using doses of 5.0, 10.0, 20.0, and 25.0 mljkg, administered by cannula, on groups of two mice each. The mice were observed from the time of dosing until the end of a 7 day period. The results of this test were used to determine doses to be used for the final study. In a preliminary study, none of the mice died. The doses of Glyceryl Ricinoleate used in the final study were 12.5, 20.0, and 25.0 mljkg. Test groups consisted of 10 mice each. Over the 7 day period, none of the mice at the lowest dose level died. In the 20.0 mljkg group one mouse died within 24 h of dosing, and two mice died between days 4 and 7 in the 25.0 mljkg group. The two mice that died in the high-dose group previously had a loss of body weight, as did others of the test animals (especially on day 7). Other signs noted in the test animals were piloerection within 30 minutes after dosing and inactivity within 2 h after dosing. All surviving animals appeared to be asymptomatic after day 7. It was concluded that the LD50 .value for Glyceryl Ricinoleate exceeded 25.0 mljkg.<72)

The acute oral toxicity of products containing Glyceryl Ricinoleate was tested in rats. In the first test, five rats were dosed by oral intubation with 15.0 gjkg of a product containing 5.6% Glyceryl Ricinoleate. The product was administered in corn oil, with a final Glyceryl Ricinoleate test concentration listed as 33.3%. None of the rats died, and all gained weight over the 7 day observation period.<73) The second test was identical to the first, except that a different unspecified product was used. As in the first test, none of the five rats died when dosed with 15.0 g/kg of the product in corn oil, and all gained weight over the 7 day observation period.<74) The third test was performed in the same manner as the first two, once again the exception being the product type tested. As the previous tests indicated, the product was nontoxic when ingested, and the five rats all gained weight during the study.<75)

Skin and Tissue Irritation

Four New Zealand white rabbits were used in a Draize skin test of Glyceryl Ricinoleate. A 0.5 ml sample of the test substance was placed on the



clipped and intact and clipped and abraded skin of each rabbit. An occlusive patch was then placed over each test site, where it remained for 24 h. The test sites were scored by the method of Draize upon the removal of the patches and 48 h later (24 and 72 h readings). The average of the two scores was the primary irritation index (PII). Two of the rabitts had very slight erythema at both the intact and abraded sites at the 24 h reading, and the reaction of the abraded site of one of these rabbits persisted through the 72 h reading. A third rabbit had well-defined erythema at both sites at the 24 h reading, with the reaction at the abraded site again persisting with the same intensity through the 72 h reading. This same rabbit also had a slight edema at the abraded site at the 72 h reading. The fourth rabbit tested had no reactions. The Pll was determined to be 0.75, and it was concluded that the Glyceryl Ricinoleate was mildly irritating.<76)

A primary irritation study with rabbits was performed on Glyceryl Ricinoleate using the solid product, undiluted, as it was supplied by the manufacturer. The Glyceryl Ricinoleate, 5.0 g, was applied to the clipped and intact (left flank) and clipped and abraded (right flank) skin of six albino New Zealand white rabbits. Composite patches were placed over the test sites, remaining in place for 24 h. The sites were graded at 24 h and again at 72 h according to the method of Draize. All rabbits had scores of 0 for both erythema and edema formation, resulting in a group total mean score and a primary irritation score of 0.0. Glyceryl Ricinoleate was thus classified as a nonirritant to the skin.<77)

The primary skin irritation of various unspecified products containing 5.6% Glyceryl Ricinoleate was tested in rabbits using an occlusive patch single-insult test procedure. The maximum obtainable Pll was 4. In the first test, the nine rabbits had scores of 0 at 2 and 24 h after removal of the patch, resulting in a group PII score of 0.00.<78) The results of the second, third, and fourth tests were identical, the group Pll being 0.00, indicating that the test products were nonirritating.<79- 81 ) In another test, rabbit 9 had a score of~ at the 2 h grading, but this had reduced to 0 by the 24 h grading. The other eight rabbits all had scores of 0 at both grading times. The group Pll was 0.06, indicating that the test material was minimally irritating.<82) In the final test, all rabbits had scores of 0 at both grading times, resulting in a group PII score of 0.00, indicating that the product tested was nonirritating.<83)

In a study of tissue irritation, injections of 0.5 ml of Glyceryl Ricinoleate were administered bilaterally into the pectoral muscle of six male Hubbard crossbred chickens weighing 3-4 pounds. On days 1, 3, and 7 postinjection, two chickens were killed and examined for the determination of gross lesions at the injection site. Sites were examined for inflammation and necrosis (scale of 1-5). Scores of 1 (three of six chickens) and 3 (two of six chickens) were reported. The right pectoral muscles of two chickens had necrotic foci (grade 5) on days 1 and 7. Glyceryl Ricinoleate caused moderate irritation and was not absorbed (i.e., the compound was visible at the treatment of sites of all six chickens).<84)

After intravenous administration of a bolus of 0.1 mljkg technical-grade ricinoleic acid into the inferior venae cavae of eight dogs, five dogs developed tachypnea (increase of at least five breaths per minute over the basal rate) and two dogs died from circulatory arrest.<85) No other clinical signs, such as



erythema, hives, edema, or defecation, were noted. Ricinoleic acid regularly produced an immediate decrease in blood pressure occasionally followed by asecond hypotensive response that was not associated with histamine release. Increased histamine ranging from 0.6 to 15.3 ngjml in the blood of seven dogs was observed within 2 minutes of administration of ricinoleic acid.

Eye Irritation

A 0.1 ml sample of Glyceryl Ricinoleate was placed into one eye of each of nine New Zealand white rabbits. Three of the rabbits had the test material rinsed from their eyes with 20 ml of lukewarm water 2 s after instillation, three rabbits had their eyes rinsed 4 s after instillation, and 3 rabbits did not have their eyes rinsed. In all the rabbits, the contralateral eye served as an untreated control. The eyes were graded for damage according to the Draize system for scoring ocular lesions at 1_, 2, 3, 4, and 7 days after instillation of the test material. No irritation was observed in the eyes that had been rinsed, and only mild irritation of the conjunctiva, lasting no longer than 24 h, was noted in the eyes that were not rinsed. <76)

Into the conjunctival sac of the right eye of each of six albino New Zealand white rabbits was instilled 0.10 g undiluted Glyceryl Ricinoleate. The left eye of each rabbit served as the untreated control. The eyes were examined at 24, 48, and 72 h after instillation of the test material, and irritation was scored according to Draize and the Federal Register 1973. An opthalmoscope was used to examine the eyes, and ultraviolet light and fluorescein dye were used to determine the incidence of corneal opacities. All test animals had scores of 0 throughout the 3 day observation period, resulting in a group mean 3 day score of 0.0. Glyceryl Ricinoleate was classified as negative for irritation or a nonirritant to the eye.<86l

A group of unspecified products, all but one containing 5.6% Glyceryl Ricinoleate (the exception contained 6.2% Glyceryl Ricinoleate), was tested for eye irritation. In the first six tests, the protocol was the same and is summarized here. The product was applied to 100% concentration to the eyes of six rabbits (per product tested). The product was applied three times, the eyes were not rinsed, and anesthesia was not used. With one exception, the eyes were scored daily for 3 days after application of the test product; in the other case, the eyes were scored for the first 4 days and again on day 7. The irritation was scored by the Draize classification of eye irritation. In test 1, all rabbits scored 0 at all times, the resulting conclusion being that the product tested did not have the potential for eye irritation.<87l In test 2, rabbit 3 had corneal opacity, iritis, and redness, swelling, and discharge of the conjunctiva (scores of 5, 5, and 4, respectively) on day 1. This resulted in a total score of 3 for the day. On days 2 and 3, all rabbits scored 0, leading to the conclusion that the product tested had a minimal irritation potential.<88l In test 3, rabbit 3 scored a 2 for conjunctival redness, swelling, and discharge on day 2, resulting in a total score of 1 for the day. On days 1 and 3, the scores were 0, leading to the conclusion that the product tested had a minimal irritation potential.<89l In test 4, the total score for day 1 was 2, with rabbit 3 having scores of 5 and 6 for corneal opacity and conjunctival redness, swelling, and discharge, respec-



tively. On days 2 and 3 all scores were 0, and it was concluded that the product tested had a minimal irritation potential.<90) In test 5, the concentration of Glyceryl Ricinoleate in the product tested was 6.2%. On day 1, rabbit 6 scored 2 for conjunctival redness, swelling, and discharge, for a group total score of 1. The same situation occurred with rabbit 2 on day 2, and the condition with this rabbit persisted into day 3. Also on day 3, rabbit 3 scored 5 for corneal opacity and 10 for conjunctival reactions. The group total score for day 3 was 3. On day 4, a conjunctival score of 2 remained for rabbit 3. By day 7, all rab.bits were scored as 0. The conclusion reached was that the product tested had a mild irritation potential.<91 ) In test 6, rabbits 1-3 scored 1 for conjunctival reactions on day 2, resulting in a group total score of 1 for that day. For days 1 and 3 the group total scores were 0, and the conclusion was that the product tested had a minimal eye irritation potential.<92) In test 7, the product was tested at a concentration of 50% in corn oil, and all scores for all rabbits were 0, indicating that the product tested did not have a potential for irritation.<93) In test 8, the product was also tested at a concentration of 50% in corn oil. On day 1, rabbits 1, 4, and 5 scored 2 for conjunctival reactions, and rabbits 2 and 6 scored 4 for the same category. The group total score for day 1 was 2. On day 2, rabbits 3 and 4 scored 2 for conjunctival reactions, and rabbits 2 and 6 remained in the same condition as the previous day. The group total score for day 2 was 2. On day 3, all rabbits scored 0. The conclusion was that the product tested had a minimal irritation potential.<94)

A final report on the "toxicity testing" of castor oil is expected from the National Toxicology Program.<95)

MUTAGENICITY AND CARCINOGENICITY

Castor oil was negative for muta~enicity when tested by the Ames assay by the National Toxicology Program.< 6)

A volume of 0.1 ml of a 2% ricinoleic acid preparation in gum tragacanth was injected intravaginally into 20 BALBjc female mice twice weekly for a total of 100 injections.<97) No tumors were seen in the 20 treated or in the 30 untreated mice. Of the 20 positive control mice treated with 0.3% 7,12-dimethylbenz(a)anthracene, also in gum tragacanth, 15 developed squamous cell carcinomas of the vagina andjor perineal skin.

Castor oil is currently being evaluated for carcinogenicity by the National Toxicology Program. <95)


Skin Irritation and Sensitization

The skin irritation potential of Glyceryl Ricinoleate was evaluated in 20 human test subjects. An unspecified product containing 5.6% Glyceryl Ricinoleate was applied at full strength to occlusive patches, which were then applied in a single insult to the test subjects. The Pll of the test product was 0.0, indicating that the product containing 5.6% Glyceryl Ricinoleate was not an irritant.<98)


ASSESSMENT: GLVCERYL RICINOLEATE 733

In a second irritation potential test, the Pll for an unspecified product containing 5.6% Glyercyl Ricinoleate was also 0.0. In this test, the number of panelists was 19, and as before, the product was applied on an occlusive patch as a single insult. Again the conclusion was that the product containing 5.6% Glyceryl Ricinoleate was not an irritant.<99>

Castor beans, the source of castor oil from which ricinoleic acid is isolated, contain a toxic polypeptide, ricin, at an approximate concentration of 3%.<100·101> Clinical cases of castor bean skin allergy and asthma have been associated with ricin or "a protein component,"<102-104> not within the ricinoleic acid component of the castor bean.

A few cases of lipstick dermatitis have been reported. A 3 + positive reaction to castor oil, an ingredient in a makeup remover, was observed upon series testing of cosmetics and their ingredients after a 23-year-old woman

____ reported acute facial dermatitis. <105> After testing with ingredients of lipsticks and lip creams, a 22-year-old

woman who had developed dry and painful cracking of the lips reacted with a 2 + response 48 and 72 h after application of castor oil.<106> In follow-up testing, this subject had similar reactions to purified castor oil, ricinoleic acid, and a 3% preparation of ricinoleic acid in petrolatum.(1o7) Tests with other fatty acids ingredients of castor oil were negative.

A 29-year-old female with a history of dermatitis to deodorant developed an acute edematous dermatitis of the lips and perioral area spreading to the entire face and neck after a few weeks of use of a lipstick product.(10B) In a series of three patch tests, the subject had 2 + reactions to a standard test series (20% colophony in petrolatum) and to the lipstick formulation in the first test, 2 + reactions to castor oil and 1% octyl-dimethyl-p-aminobenzoic acid in petrolatum, and a 3 + reaction to 0.5% aqueous allantoin in the second test. The third test resulted in a 3 + reaction to castor oil, a severe (3 +) spreading reaction to 30% ricinoleic acid in petrolatum, and negative responses to the p-aminobenzoic acid derivative and allantoin preparations.

Other cases of dermatitis resulting from the same lipstick formulation were reported previously.<109> A 53-year-old male with no history of skin disease developed periorbital and facial edema with lesions on the lips and in the nose. A 36-year-old male with no history of skin disease developed a severe dermatitis on the lips and around the mouth. A 37-year-old female with a family history of psoriasis and hand eczema developed severe, vesicular dermatitis on the lips and around the mouth. All three subjects had 2 + reactions to the lipstick formulation and to "a microcrystalline wax" ingredient of unknown composition.

SUMMARY

Glyceryl Ricinoleate is the monoester of glycerol and ricinoleic acid. It is an oily liquid with a characteristic odor.

Glyceryl Ricinoleate is most frequently used in cosmetic as a base ingredient in lipsticks and as a pigment binder in eye shadows. Its use in cosmetic



formulations has been reported at concentrations between 0.1 and 50%. In 1986, it was used in a total of 34 cosmetic formulations.

Monoglycerides of edible fats and oils are generally recognized as safe for use as emulsifying agents and food additives. Glyeryl Ricinoleate is listed by the FDA as an inactive ingredient in drug preparations. Castor oil is used as an active ingredient in some OTC wart-removing products, and ricinoleic acid is used in some OTC vaginal contraceptives. Castor oil is also considered a safe and effective laxative when taken orally as a single dose.

Upon ingestion, Glyceryl Ricinoleate is absorbed into the intestinal mucosa. Increased doses of castor oil result in decreased absorption by the intestine.

Ricinoleic acid appears to be preferentially incorporated into the triglycerides rather than the phospholipids.

Metabolically, ricinoleic acid may be degraded by ,8-oxidation into acetyi-CoA and a dodecanoyi-CoA. This dodecanoic acid may be further metabolized either by hydration followed by oxidation and cleavage or by isomerization of the double bond. Another metabolic pathway involving the a-oxidation of a carbon unit from the carboxyl terminus of the fatty acid has also been observed.

Acute oral toxicity tests indicated that Glyceryl Ricinoleate has an LD50

greater than 25.0 mljkg in mice and that products containing 5.6% Glyceryl Ricinoleate were not toxic when ingested.

The feeding of castor oil to rats results in the presence of hydroxystearic acid in the feces. The hydroxystearic acid is probably formed by bacterial hydrogenation of ricinoleic acid.

The hydrolysis of castor oil and Glyceryl Ricinoleate in the small intestine releases ricinoleic acid; ricinoleic acid is the active cathartic ingredient in castor oil. The mechanisms of the carthartic action of ricinoleic acid are currently being studied.

Glyceryl Ricinoleate, when evaluated by a Draize skin test, was a mild irritant to rabbits. In a primary skin irritation test in rabbits, Glyceryl Ricinoleate was classified as a nonirritant.

When rabbits were tested with products containing 5.6% Glyercyl Ricinoleate in a single-insult occlusive patch test, the products had either no (four of five tests) or mild (one of five tests) irritation potentials.

Injection of Glyceryl Ricinoleate into the pectoral muscles of chickens caused mild irritation at the site of injection, but no Glyceryl Ricinoleate was absorbed.

Glyceryl Ricinoleate was nonirritating to rabbit eyes in a primary eye irritation test, and in a Draize test, it was mildly irritating to rabbit eyes from which it was not rinsed but nonirritating to rabbit eyes from which it had been rinsed 2 and 4 s after instillation. Various products containing Glyceryl Ricinoleate were tested for irritation potential in rabbit eyes. Of eight tests, two products demonstrated no irritation potential, five products had a minimal irritation potential, and one product had a mild irritation potential.

Castor oil was nonmutagenic by the Ames test. Carcinogenicity testing in female mice using ricinoleic acid, a possible constituent ingredient of spermicidal preparations, yielded negative results.



In human single-insult occlusive patch tests, no indication of skin irritation potential was observed in the two products tested (each contained 5.6% Glyeryl Ricinoleate).

There have been several reported instances of lipstick dermatitis, and castor oil and ricinoleic acid have been implicated in clinical patch test studies on patients experiencing dermatitis, and occasional facial edema, from the use of I i psticks.

DISCUSSION

Section 1 Paragraph (p) of the Cl R Procedures states that "A lack of information about an ingredient shall not be sufficient to justify a determination of safety." In accordance with Section 30(j)(2)(A) of the Procedures, the expert panel informed the public of its decision that the data on Glyceryl Ricinoleate were insufficient to determine that this ingredient, under each relevant condition of use, was either safe or not safe. The panel issued a "Notice of Insufficient Data" on January 29, 1987, outlining the data needed to assess the safety of Glyceryl Ricinoleate. The types of data required included:

1. Guinea pigs 28 day chronic dermal toxicity 2. Clinical sensitization and photosensitization studies (or an appropriate

ultraviolet spectrum instead of the photosensitization data)

There has been no response or indication of intent to supply the aforementioned information.

CONCLUSION

The CIR Expert Panel concludes that the available data are insufficient to support the safety of Glyceryl Ricinoleate as used in cosmetics.

REFERENCES

1. ESTRIN, N.F., CROSLEY, P.A., and HAYNES, CR. (eds.). (1982). Cosmetic, Toiletry and Fragrance Association Cosmetic Ingredient Dictionary, 3rd ed. Washington, D.C.: The Cosmetic, Toiletry and Fragrance Association.

2. ESTRIN, N.F., HAYNES, CR., and WHELAN, j.M. (eds.). (1982). CTFA Compendium of Cosmetic Ingredient Compositions. Cosmetic Ingredient Descriptions. Washington, D.C.: The Cosmetic, Toiletry and Fragrance Association.

3. WEAST, R.C. (1984). CRC Handbook of Chemistry and Physics, 65th ed., 1984-1985. Boca Raton, FL: CRC press, p. C-314.

4. GREENBERG, L.A., and LESTER, D. (1954). Handbook of Cosmetic Materials. New York: lnterscience. 5. GRAYSON, M. (1984). Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 11. New York: john

Wiley and Sons, p. 931.



6. SENZEL, A.j. (ed.). (1977). Newburger's Manual of Cosmetic Analysis, 2nd ed. Washington, D.C.: AOAC.

7. PAULUS, G.L. and CHAMPION, M.H. (1972). Gas-liquid chromatographic determination of castor oil as methyl ricinoleate in lipstick. j. Soc. Cosmet. Chem. 23, 313-9.

8. BINDER, R.G., APPLEWHITE, T.H., KOHLER, G.O., and GOLDBLATT, L.A. (1962). Chromatographic analysis of seed oils. Fatty acid composition of castor oil. j. Am. Oil Chem. Soc. 39, 513-7.

9. KRESZE, G., BEDERKE, K., and SCHAEVFFELHUT, F. (1965). Analysis of mixtures of mono- and diglycerides by gas chromatography and nuclear magnetic resonance. Z. Anal. Chem. 209(2), 329-37.

10. TEUPEL, M., POLLERBERG, j. (1968). Analysis of ricinoleic acid monoglycerides by column chromatoraphy and nuclear magnetic resonance spectroscopy (German abstract). Tenside 5(9-10), 275-8.

11. KING, j.W., ADAMS, E.C., and BIDLINGMEYER, B.A. (1982). Determination of free fatty acids in natural oils and alkyd resins by high-performance liquid chromatography. j. Liquid Chromatogr. 5(2), 275-304.

12. HORWITZ, W. (ed.). (1980). Official Methods of Analysis of the Association of Official Analytical Chemists (AOAC), 13th ed. Washington, D.C.: AOAC.

13. ACHAYA, K.T. (1971). Chemical derivatives of castor oil. j. Am. Oil. Chem. Soc. 48(11), 758-63. 14. RONDEAU, R. (1968). La lipochimie de l'huile de ricin. Rev. Fr. Corps Gras 15(8-9), 529-37. 15. SWERN, D. (ed.). (1979). Bailey's Industrial Oil and Fat Products, Vol. 1, 4th ed. New York: john Wiley

and Sons. 16. WINDHOLZ, M., BUDAVARI, S., BLUMETTI, R.F., and OTTERBEIN, E.S. (eds.). (1983). The Merck Index,

10th ed. Rahway, NJ: Merck and Co. 17. HUNTING, A.L.L. (1983). Encyclopedia of Shampoo Ingredients. Cranford, Nj: Micelle Press. 18. RAMOS, L.C., TANGO, j.S., SA VI, A., and LEAL, N.R. (1984). Variability for oil and fatty acid composi

tion in castor bean varieties. j. Am. Oil Chem. Soc. 61(12), 1841-3. 19. FOOD AND DRUG ADMINISTRATION (FDA). (1986). Cosmetic product formulation data table. 20. EIERMANN, H.j. Oune 12, 1986). Acting Director, Division of Colors and Cosmetics, Food and Drug

Administration. Letter to R.L. Elder, of Cosmetic Ingredient Review, on oleic acid group, methylene chloride, and Glyceryl Ricinoleate. Available for review: Director, Cosmetic Ingredient Review, 1110 Vermont Ave., N.W., Suite 810, Washington, D.C. 20005.

21. CODE OF FEDERAL REGULATIONS (CFR). (1984). Title 21. Food and Drugs. Parts 175.105, 176.170, 176.210, 178.3130, 182.90, 182.4505, 720.4.

22. BROWN, ).L. (1983). Incomplete labeling of pharmaceuticals: A list of "inactive" ingredients. N. Engl.). Med. 309(7), 439-41.

23. FEDERAL REGISTER. (Sept. 3, 1982). Wart remover drug products for OTC human use; tentative final monograph. 47(172), 39103.

24. FEDERAL REGISTER. (May 24, 1972). Certain OTC vaginal contraceptives. Drugs for human use; drug efficacy study implementation. 37(101), 10525.

25. SCARPA, A., and GUERCI, A. (1982). Various uses of the castor oil plant (Ricinus communis L.). A review.). Ethnopharmacol. 5(2), 117-37.

26. BLACOW, N.W. (1972). Martindale. The Extra Pharmacopeia, 26th ed. London: Pharmaceutical Press, p. 1256.

27. FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY (FASEB), Life Sciences Research Office. (1975). Evaluation of the health aspects of glycerin and glycerides as food ingredients. U.S. Department of Commerce. NTIS PB-254536.

28. WATSON, W.C., GORDON, R.S., Jr., KARMEN, A., and )OYER, A. (1963). The absorption and excretion of castor oil in man. j. Pharm. Pharmacal. 15, 183-8.

29. FLORKIN, M., and STOTZ, E. H. (eds.). (1971). Lipid Metabolism, Vol. 18, Comprehensive Biochemistry. New York: Elsevier.

30. ELDER, R.L. (ed.). (1982). Final report on the safety assessment of decyl and isodecyl oleates. j. Am. Coli. Toxicol. 1(2), 85-95.

31. COSMETIC INGREDIENT REVIEW. (Nov. 13, 1985). Final report on glyceryl oleate. Available for review: Director, Cosmetic Ingredient Review, 1110 Vermont Ave., N.W., Suite 810, Washington, D.C. 20005.

32. WATSON, W.C., and GORDON, R.S., Jr. (1962). Studie~ 1:m the digestion, absorption and metabolism of castor oil. Biochem. Pharmacal. 11, 229-36. ·

33. RAO, M.K.G., RISSER, N., and PERKINS, E.G. (1969). The Incorporation of ricinoleic acid into rat lymph lipids. Proc. Soc. Exp. Bioi. Med. 131(4), 1369-72.

34. GAGINELLA, T.S., and PHILLIPS, S.F. (1975). Ricinoleic i!cid: Current view of an ancient oil. Am. j. Dig. Dis. 20(12), 1171-7.



35. AMMON, H.V., THOMAS, P.j., and PHILLIPS, S.F. (1974). Effects of oleic and ricinoleic acid on net jejunal water and electrolyte movement. ). Clin. Invest. 53, 374-9.

36. KISHIMOTO, Y., AND RADIN, N.S. (1963). Occurrence of 2-hydroxy fatty acids in animal tissues. j. Lipid Res. 4(2), 139-43.

37. AKANUMA, H., and KISHIMOTO, Y. (1979). Synthesis of ceramides and cerebrosides containing both alpha-hydroxy and non-hydroxy fatty-acids from lignoceroyi-CoA by rat-brain microsomes. ). Bioi. Chern. 254(4), 1050-6.

38. STEWART, W.C., and SINClAIR, R.G. (1945). The absence of ricinoleic acid from phospholipids of rats fed castor oil. Arch. Biochem. 89, 7-11.

39. WATSON, W.C., and MURRAY, E.S. (1965). Triricinolein synthesis in vivo. Biochim. Biophys. Acta 106(2), 311-4.

40. BARBER, E.D., SMITH, W.L., and lANDS, W.E.M. (1971). Incorporation of ricinoleic acid into glycerolipids. Biochim. Biophys. Acta 248(2), 171-9.

41. HAlLABA, E., AL -SUHYBANI, A., ABDULLAH, M.E., and ZAKI, F.S. (1985). labelling of castor oil for myocardial study. j. Radioanal. Nucl. Chern. 89(1), 97-107.

42. PAUl, H., and McCAY, C.M. (1942). The utilization of fats by herbivora. Arch. Biochem. Biophys. 1, 247. 43. PERKINS, E.G., ENDRES, j.G., and KUMMEROW, F.A. (1961). The metabolism of fats. I. Effect of dietary

hydroxy acids and their triglycerides on growth, carcass, and fecal fat composition in the rat.). Nutr. 73, 291.

44. NUTRITION REVIEWS. (1970). Oxidation of unsaturated fatty acids. 28(6), 165-67. 45. MORRIS, L.j. (1970). Mechanisms and stereochemistry in fatty acid metabolism. Biochem. j. 118(5),

681-93. 46. BOWEN, D.M., and RADIN, N.S. (1968). Hydroxy fatty acid metabolism in the brain. Adv. lipid Res. 6,

255-72. 47. FUlCO, A.j. (1974). Metabolic alterations of fatty acids. Annu. Rev. Biochem. 43, 215-41. 48. LEKAKIS, N.J. (1977). Alpha-oxidation of fatty acids in Escherichia coli. FEMS Microbial. Lett. 1(5),

289-92. 49. GUNSTONE, F.D. (1967). An Introduction to the Chemistry and Biochemistry of Fatty Acids and Their

Glycerides. Great Britain: Richard Clay (The Chancer Press) Ltd. 50. UCHIYAMA, M., SATO, R., and MIZUGAKI, M. (1963). Biochim. Biophys. Acta 70,344-6. 51. OKUI, S., UCHIYAMA, M., SATO, R., and MIZUGAKI, M. (1964). j. Biochem. 55,81-6. 52. OKUI, S., UCHIYAMA, M., and MIZUGAKI, M. (1963). j. Biochem. 53, 265-70. 53. MIZUGAKI, M., FUKUY AMA, H., SAKAMOTO, T., and YAMANAKA, H. (1978). Studies on the

metabolism of unsaturated fatty acids. I. Synthesis and identification of 6-hydroxydodec-3-cis-enoic acid, the final metabolite of ricinoleic acid by Escherichia coli K-12. Chern. Pharm. Bull. 6(8), 2417-21.

54. JAMES, A.T., WEBB, j.P.W., and KELlOCK, T.D. (1961). The occurrence of unusual fatty acids in fecal lipids from human beings with normal and abnormal fat absorption. Biochem. j. 78, 333-9.

55. SOONG, C.S., THOMPSON, j.B., POLEY, j.R., and HESS, D.R. (1972). Hydroxy fatty acids in human diarrhea. Gastroenterology 63, 748-57.

56. KIM, Y.S., and SPRITZ, N. (1968). Metabolism of hydroxy fatty acids in dogs with steatorrhea secondary to experimentally produced intestinal blind loops. ). lipid Res. 9, 487-91.

57. THOMAS, P.j. (1972). Identification of some enteric bacteria which convert oleic acid to hydroxystearic acid in vitro. Gastroenterology 62, 430-5.

58. INFORMATICS. (1973). Monograph on glycerine and glycerides. DHEW Contract No. FDA 72-104. NTIS PB-221 227/2.

59. MEYER, H. (1890). Ueber den wirksamen bestandtheil des ricinusols. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 28, 145-521. (Cited in Ref. 67.)

60. BRIGHT-ASARE, P., and BINDER, H.j. (1973). Stimulation of colonic secretion of water and electrolytes by hydroxy fatty acids. Gastroenterology 64, 81-8.

61. AMMON, H.V., and PHILLIPS, S.F. (1973). Inhibition of colonic water and electrolyte absorption by fatty acids in man. Gastroenterology 65, 744-9.

62. AMMON, H.V., and PHILLIPS, S.F. (1974). Inhibition of ileal water absorption by intraluminal fatty acids. j. Clin. Invest. 53, 205-10.

63. STEWART, j.j., GAGINEllA, T.S., OlSEN, W.A., and BASS, P. (1975). Inhibitory actions of laxatives on motility and water and electrolyte transport in the gastrointestinal tract. j. Pharmacal. Exp. Ther. 192, 458-67.



64. STEWART, J.j., GAGINELLA, T.S., and BASS, P. (1975). Actions of ricinoleic acid and structurally related fatty acids on the gastrointestinal tract. I. Effects on smooth muscle contractility in vitro. j. Pharmacal. Exp. Theor. 195(2), 347-54.

65. GAGINELLA, T.S., HADDAD, A.C., GO, V.L., and PHILLIPS, S.F. (1977). Cytotoxicity of ricinoleic acid (castor oil) and other intestinal secretagogues on isolated intestinal epithelial cells. j. Pharmacal. Exp. Ther. 201 (1 ), 259-66.

66. GAGINELLA, T.S., and PHILLIPS, S.F. (1976). Ricinoleic acid (castor oil) alters intestinal surface structure. A scanning electron microscopic study. Mayo Clin. Proc. 51,6-12.

67. GAGINELLA, T.S., STEWART, j.j., OLSEN, W.A., and BASS, P. (1975). Actions of ricinoleic acid and structurally related fatty acids on the gastrointestinal tract. II. Effects on water and electrolyte absorption in vitro. j. Pharmacal. Exp. Ther. 195(2), 355-61.

68. COHEN, M.M. (1982). The effect of cathartics on prostaglandin synthesis by rat gastrointestinal tract. Prostaglandins Leukotrienes Med. 8(4), 389-97.

69. BRETAGNE, j.F., VIDON, N., L'HIRONDEL, C., BERNIER, j.j., BOVET, M., MAUREL, M., RONGIER, M., and ROUCHETTE, j. (1981). Increased cell loss in the human jejunum induced by laxatives (ricinoleic acid, dioctyl sodium sulphosuccinate, magnesium sulphate, bile salts). Gut 22, 264-9.

70. FEDERAL REGISTER. (March 21, 1975). Proposal to establish monographs for OTC laxative, antidiarrheal, emetic, and antiemetic products. 40(56), 12909-10.

71. PIETRUSKO, R.G. (1977). Use and abuse of laxatives. Am. j. Hosp. Pharm. 34(3), 291-300. 72. DYNAMIT NOBEL A.G. (1977). Acute oral toxicity evaluation of Softigen 701 in the mouse. Unpub

lished data submitted to CTFA. 73. COSMETIC, TOILETRY AND FRAGRANCE ASSOCIATION (CTFA). (1979). Acute oral toxicity of a

product containing Glyceryl Ricinoleate. Washington, D.C. Test no. 26/63. 74. CTFA. (1979). Acute oral toxicity of a product containing Glyceryl Ricinoleate. Washington, D.C. Test

no. 26/64. 75. CTFA. (1980). Acute oral toxicity of a product containing Glyceryl Ricinoleate. Washington, D.C. Test

no. OT29/68. 76. DYNAMIT NOBEL A. G. (1972). Softingen 701: Draize eye test, Draize skin test. Unpublished data

submitted to CTFA. 77. DYNAMIT NOBEL A.G. (1980). Primary skin irritation test in the rabbit. Unpublished data submitted to

CTFA. 78. CTFA. (1979). Primary skin irritation in rabbits of a product containing Glyceryl Ricinoleate. Washing

ton, D.C. Test no. S11/117, product 05C/16813-01. 79. CTFA. (1979). Primary skin irritation in rabbits of a product containing Glyceryl Ricinoleate. Washing




ton, D.C. Test no. S12/37. 83. CTFA. (1980). Primary skin irritation in rabbits of a product containing Glyceryl Ricinoleate. Washing

ton, D.C. Test no. S12/56. 84. HEM, S.L., BRIGHT, D.R., BANKER, G.S., and POGUE, j.P. (1975). Tissue irritation evaluation of

potential parenteral vehicles. Drug Dev. Commun. 1(5), 471-7. 85. LORENZ, W., SCMAL, A., SCHULT, H., LANG, S., OHMANN, C., WEBSTER, D., KAPP, B., LUEBEN, L.,

and DOENICKE, A. (1982). Histamine release and hypotensive reactions in dogs by solubilizing agents and fatty acids: Analysis of various components in cremophor EL and development of a compound with reduced toxicity. Agents Actions 12, 64-80.

86. DYNAMIT NOBEL A.G. (1980). Primary eye irritation test in the rabbit. Unpublished data submitted to CTFA.

87. CTFA. (1979). Eye irritation of a product containing Glyceryl Ricinoleate. Washington, D.C. Test no. E43/71.

88. CTFA. (1979). Eye irritation. of a product containing Glyceryl Ricinoleate. Washington, D.C. Test no. 43/70.



ASSESSMENT: CLYCERYl RICINOLEATE 739



92. CTFA. (1979). Eye irritation of a product containing Glyceryl Ricinoleate. Washington, D.C. Test no. 43/221.



95. NATIONAL TOXICOLOGY PROGRAM (NTP). (April 28, 1986). Telephone inquiry on status of toxicity testing of castor oi I by NTP.

96. NTP. (1985). National Toxicology Program: Fiscal Year 1985 Plan. Chemical test results for mutagenicity in Salmonella assays in FY 1984. Washington, D.C.: U.S. Department of Health and Human Services, p. 63.

97. BOYLAND, E., ROE, F.).C., and MITCHLEY, B.C.V. (1966). Test of certain constituents of spermicides for carcinogenicity in genital tract of female mice. Br. ). Cancer 20(1), 184-9.

98. CTFA. (1979). Skin irritation potential (human patch test) of a product containing Glyceryl Ricinoleate. Washington, D.C. Test no. 4527/4.

99. CTFA. (1980). Skin irritation potential (human patch test) of a product containing Glyceryl Ricinoleate. Washington, D.C. Test no. 4527/46.

100. RAMAKRISHNAN, S., BALASUBRAMANIAN, K., and MADHAVAN, M. (1972). Biochemical and pathological studies on castor seed poisoning.). Assoc. Physicians India 20(10), 781-4.

101. EL MAHOUB, M., KHALIFA, M.M., JASWAL, O.B., and GARRAH, M.S. (1983). "Ricin syndrome." A possible new teratogenic syndrome associated with ingestion of castor oil seed in early pregnancy: A case report. Ann. Trap. Paediatr. 3: 57-61.

102. LEHRER, S.B., KARR, R.M., and SALVAGGIO, ).E. (1981). Analysis of green coffee bean and castor bean allergens using RAST inhibition. Clin. Allergy 11(4), 357-66.

103. DAVISON, A.G., BRITTON, M.G., FORRESTER, ).A. DAVIES, R.)., and HUGHES, D.T.D. (1983). Asthma in merchant seamen and laboratory workers caused by allergy to castor beans (Ricinus communis): Analysis of allergens. Clin. Allergy 13(6), 553-62.

104. KEMENY, D.M., FRANKLAND, A.W., FAHKRI, Z.l., and TRULL, A.K. (1981). Allergy to castor bean in the Sudan: Measurement of serum lgE and specific lgE antibodies. Clin. Allergy 11(5), 463-71.

105. BRANDLE, 1., BOU)NAH-KHOUAD)A, A., and FOUSSEREAU, ). (1983). Allergy to castor oil. Contact Dermatitis 9(5), 424-5.

106. SAl, S. (1983). lipstick dermatitis caused by castor oil. Contact Dermatitis 9(1), 75. 107. SAl, S. (1983). Lipstick dermatitis caused by ricinoleic acid. Contact Dermatitis 9(6), 524. 108. ANDERSEN, K.E., and NIELSEN, R. (1984). Lipstick dermatitis related to castor oil. Contact Dermatitis

11 ( 4), 253-4. 109. de DARKO, E., and OSMUNDSEN, P.E. (1984). Allergic contact dermatitis to lipcare® lipstick. Contact

Dermatitis 11(1), 46.


International Journal of Toxicology, 26(Suppl. 3):31–77, 2007Copyright c© American College of ToxicologyISSN: 1091-5818 print / 1092-874X onlineDOI: 10.1080/10915810701663150

Final Report on the Safety Assessment of Ricinus Communis(Castor) Seed Oil, Hydrogenated Castor Oil, GlycerylRicinoleate, Glyceryl Ricinoleate SE, Ricinoleic Acid,Potassium Ricinoleate, Sodium Ricinoleate, ZincRicinoleate, Cetyl Ricinoleate, Ethyl Ricinoleate, GlycolRicinoleate, Isopropyl Ricinoleate, Methyl Ricinoleate, andOctyldodecyl Ricinoleate1

The oil derived from the seed of the Ricinus communis plantand its primary constituent, Ricinoleic Acid, along with certain ofits salts and esters function primarily as skin-conditioning agents,emulsion stabilizers, and surfactants in cosmetics, although otherfunctions are described. Ricinus Communis (Castor) Seed Oil isthe naming convention for castor oil used in cosmetics. It is pro-duced by cold pressing the seeds and subsequent clarification ofthe oil by heat. Castor oil does not contain ricin because ricin doesnot partition into the oil. Castor oil and Glyceryl Ricinoleate ab-sorb ultraviolet (UV) light, with a maximum absorbance at 270 nm.Castor oil and Hydrogenated Castor Oil reportedly were used in769 and 202 cosmetic products, respectively, in 2002; fewer useswere reported for the other ingredients in this group. The highestreported use concentration (81%) for castor oil is associated withlipstick. Castor oil is classified by Food and Drug Administration(FDA) as generally recognized as safe and effective for use as astimulant laxative. The Joint Food and Agriculture Organization(FAO)/World Health Organization (WHO) Expert Committee onFood Additives established an acceptable daily castor oil intake(for man) of 0 to 0.7 mg/kg body weight. Castor oil is hydrolyzed inthe small intestine by pancreatic enzymes, leading to the release ofglycerol and Ricinoleic Acid, although 3,6-epoxyoctanedioic acid,3,6-epoxydecanedioic acid, and 3,6-epoxydodecanedioic acid alsoappear to be metabolites. Castor oil and Ricinoleic Acid can en-hance the transdermal penetration of other chemicals. Althoughchemically similar to prostaglandin E1, Ricinoleic Acid did not havethe same physiological properties. These ingredients are not acutetoxicants, and a National Toxicology Program (NTP) subchronicoral toxicity study using castor oil at concentrations up to 10% inthe diet of rats was not toxic. Other subchronic studies of castoroil produced similar findings. Undiluted castor oil produced min-imal ocular toxicity in one study, but none in another. Undilutedcastor oil was severely irritating to rabbit skin in one study, onlyslightly irritating in another, mildly irritating to guinea pig and rat

Received 14 May 2007; accepted 24 August 2007.Address correspondence to Wilbur Johnson, Jr., Senior Scientific

Analyst and Writer, Cosmetic Ingredient Review, 1101 17th Street,NW, Suite 412, Washington, DC 20036, USA.

1Reviewed by the Cosmetic Ingredient Review Expert Panel.

skin, but not irritating to miniature swine skin. Ricinoleic Acid wasnonirritating in mice and in one rabbit study, but produced well-defined erythema at abraded and intact skin sites in another rabbitstudy. Zinc Ricinoleate was not a sensitizer in guinea pigs. Neithercastor oil nor Sodium Ricinoleate was genotoxic in bacterial ormammalian test systems. Ricinoleic Acid produced no neoplasmsor hyperplasia in one mouse study and was not a tumor promoter inanother mouse study, but did produce epidermal hyperplasia. Cas-tor oil extract had a strong suppressive effect on S180 body tumorsand ARS ascites cancer in male Kunming mice. No dose-relatedreproductive toxicity was found in mice fed up to 10% castor oilfor 13 weeks. Female rats injected intramuscularly with castor oilon the first day after estrus had suppressed ovarian folliculogenesisand anti-implantation and abortive effects. Castor oil used as a ve-hicle control in rats receiving subcutaneous injections had no effecton spermatogenesis. A methanol extract of Ricinus communis var.minor seeds (ether-soluble fraction) produced anti-implantation,anticonceptive, and estrogenic activity in rats and mice. Clinically,castor oil has been used to stimulate labor. Castor oil is not a signif-icant skin irritant, sensitizer, or photosensitizer in human clinicaltests, but patients with occupational dermatoses may have a pos-itive reaction to castor oil or Ricinoleic Acid. The instillation of acastor oil solution into the eyes of nine patients resulted in mildand transient discomfort and minor epithelial changes. In anotherstudy involving 100 patients, the instillation of castor oil producedcorneal epithelial cell death and continuity breaks in the epithelium.Because castor oil contains Ricinoleic Acid as the primary fatty acidgroup, the Cosmetic Ingredient Review (CIR) Expert Panel consid-ered the safety test data on the oil broadly applicable to this entiregroup of cosmetic ingredients. The available data demonstrate fewtoxic effects. Although animal studies indicate no significant irri-tant or sensitization potential, positive reactions to Ricinoleic Acidin selected populations with identified dermatoses did suggest thatsensitization reactions may be higher in that population. Overall,however, the clinical experience suggests that sensitization reac-tions are seen infrequently. In the absence of inhalation toxicitydata on these ingredients, the Panel determined that these ingre-dients can be used safely in aerosolized cosmetic products becausethe particle sizes produced are not respirable. Overall, the CIRExpert Panel concluded that these cosmetic ingredients are safe inthe practices of use and concentrations as described in this safetyassessment.

31



INTRODUCTIONThe safety of the following ingredients in cosmetics is re-

viewed in this report: Ricinus Communis (Castor) Seed Oil,Hydrogenated Castor Oil, Glyceryl Ricinoleate, Glyceryl Ri-cinoleate SE, Ricinoleic Acid, Potassium Ricinoleate, SodiumRicinoleate, Zinc Ricinoleate, Cetyl Ricinoleate, Ethyl Rici-noleate, Glycol Ricinoleate, Isopropyl Ricinoleate, Methyl Ri-cinoleate, and Octyldodecyl Ricinoleate. For the sake of brevity,Ricinus Communis (Castor) Seed Oil will be referred to as castoroil.

Glyceryl Ricinoleate and Glyceryl Ricinoleate SE are es-ters of glycerin and Ricinoleic Acid (component of castor oil).A Cosmetic Ingredient Review (CIR) safety assessment (Elder1988) of Glyceryl Ricinoleate in cosmetics was published withthe conclusion that the available data are insufficient to supportthe safety of this ingredient as used in cosmetics. The follow-ing data were needed for completion of this safety assessment:(1) 28-day chronic dermal toxicity (guinea pigs) and (2) clinicalsensitization and photosensitization studies (or an appropriateultraviolet spectrum instead of the photosensitization data).

Glyceryl Ricinoleate and Glyceryl Ricinoleate SE are in-cluded in the present safety assessment in the expectation thatthe available data on castor oil, Ricinoleic Acid, salts of Rici-noleic Acid, and other esters of Ricinoleic Acid will contributeto a resolution of the CIR Expert Panel’s data needs for GlycerylRicinoleate and Glyceryl Ricinoleate SE.

CHEMISTRY

Definition and StructureRicinus Communis (Castor) Seed Oil

According to the International Cosmetic Ingredient Dictio-nary and Handbook (Gottschalck and McEwen 2004), RicinusCommunis (Castor) Seed Oil (CAS no. 8001-79-4) is defined asthe fixed oil that is obtained from the seeds of Ricinus communis.Other names for this oil include: Castor Oil, Castor Oil (Ricinuscommunis L.), Castor Seed Oil, Ricinus Communis, and RicinusCommunis Oil (Gottschalck and McEwen 2004), and RicinusOil (TNO BIBRA International Ltd. 1999). As given by TNOBIBRA International Ltd. (1999), the structural formula is:

CH2OR||CHOR||CH2OR

where R represents a fatty acyl group [CH3(CH2)5CH(OH)CH2CH=CH(CH2)7COOH] that is typically derived from Ri-cinoleic Acid. Ricinoleic Acid accounts for 87% to 90% ofthe fatty acyl groups, and the following other fatty acids com-prise the remaining fatty acyl groups: oleic acid (2% to 7%),linoleic acid (3% to 5%), palmitic acid (1% to 2%), stearicacid (1%), dihydrostearic acid (1%), and trace amounts of other

fatty acyl groups (not specified) (TNO BIBRA International Ltd.1999).

According to other sources, Castor Oil contains 2.4% lau-ric acid (Larsen et al. 2001), 2% to 5% linoleic acid (Maieret al. 1999), and globulin, cholesterol, lipase, vitamin E, andβ-sitosterol (Scarpa and Guerci 1982).

Hydrogenated Castor OilAccording to the International Cosmetic Ingredient Dictio-

nary and Handbook (Gottschalck and McEwen 2004), Hydro-genated Castor Oil (CAS no. 8001-78-3) is defined as the endproduct of controlled hydrogenation of Ricinus Communis (Cas-tor) Seed Oil. Castor Oil, Hydrogenated is another technicalname for this ingredient, and Castor Wax (trade name) and Mon-tane 481 (trade name mixture) are other names under which Hy-drogenated Castor Oil is marketed (Gottschalck and McEwen2004).

Ricinoleic Acid, Its Salts, and Simple EstersTable 1 includes the structures, definitions, and cosmetic

ingredient functions of Glyceryl Ricinoleate, Glyceryl Rici-noleate SE, Ricinoleic Acid, Potassium Ricinoleate, SodiumRicinoleate, Zinc Ricinoleate, Cetyl Ricinoleate, Ethyl Rici-noleate, Glycol Ricinoleate, Isopropyl Ricinoleate, Methyl Ri-cinoleate, and Octyldodecyl Ricinoleate.

Chemical and Physical PropertiesProperties of castor oil and Hydrogenated Castor Oil are

summarized in Table 2 and properties of the following ingre-dients are summarized in Table 3: Ricinoleic Acid, Ethyl Ri-cinoleate, Methyl Ricinoleate, Sodium Ricinoleate, PotassiumRicinoleate, and Zinc Ricinoleate.

Composition/ImpuritiesCastor Oil

The following three peaks were observed in a gas-liquid chro-matogram on castor oil: palmitic acid (1.7%), C18 acids (stearic,oleic, and linoleic acids) (15.9%), and Ricinoleic Acid (82.4%)(Kato and Yamaura 1970).

According to the Food Chemicals Codex (National Academyof Sciences 1996), the requirements for castor oil are as follows:free fatty acids (passes test), heavy metals, as Pb (not more than10 mg/kg), hydroxyl value (between 160 and 168), iodine value(between 83 and 88), saponification value (between 176 and185), and specific gravity (between 0.952 and 0.966). The test forfree fatty acids is described as follows: free fatty acids (10 g) aredissolved in 50 ml of a mixture of equal volumes of alcohol andether (which has been neutralized to phenolphthalein with notmore than 7 ml of 0.1 N sodium hydroxide). Phenolphthalein (1ml) is added, followed by titration with 0.1 N sodium hydroxideuntil the solution remains pink (after shaking).

Similarly, the United States Pharmacopeia (Committee ofRevision of the United States Pharmacopeial Convention 2004a)


CASTOR OIL 33

TABLE 1Structures, definitions, and functions of ricinoleic acid, its salts, and esters (Gottschalck and McEwen 2004)

Structure Definition Function

CH(CH2)7COOH

OH

CH3(CH2)5CHCH2CH Ricinoleic Acid (CAS nos. 141-22-0 and 7431-95-0) is anunsaturated fatty acid. Other names include:12-Hydroxy-9-Octadecenoic Acid; 9-Octadecenoic Acid,12-Hydroxy-; Ricinic Acid; and Ricinolic Acid

Surfactant–cleansingagent

CH(CH2)5CH3

CH(CH2)7C OCH2CHCH2OH

OH

CH2CH

O

OH

Glyceryl Ricinoleate (CAS nos.141-08-2, 1323-38-2, and5086-52-2) is the monoester of glycerin and ricinoleic acid.Other names include: Glycerin Monoricinoleate; GlycerolMonoricinoleate; Glyceryl Monoricinoleate,12-Hydroxy-9-Octadecenoic Acid, Monoester with1,2,3-Propanediol; Ricinoleic Acid Monoglyceride; andRicinolein, 1-Mono-

Skin-conditioningagent—emollient andsurfactant–emulsifying agent

See above Glyceryl Ricinoleate SE is a self-emulsifying grade of GlycerylRicinoleate containing sodium and/or potassium stearate

Skin-conditioningagent—emollient andsurfactant–emulsifying agent

CH(CH2)7COOK

OH

CH3(CH2)5CHCH2CH Potassium Ricinoleate (CAS no. 7492-30-0) is the potassium saltof Ricinoleic Acid. Other names include:12-Hydroxy-9-Octadecenoic Acid, Monopotassium Salt and9-Octadecenoic Acid, 12-Hydroxy-, Monopotassium Salt

Surfactant–cleansingagent and surfactant–emulsifyingagent

See above, exceptwith Na in placeof K

Sodium Ricinoleate (CAS no. 5323-95-5) is the sodium salt ofRicinoleic Acid. Other names include:12-Hydroxy-9-Octadecenoic Acid, Sodium Salt; 9-OctadecenoicAcid, 12-Hydroxy, Sodium Salt; and Sodium Ricinate

Surfactant–cleansingagent and surfactant–emulsifying agent

CH3(CH2 )5CHCH2CH CH(CH2)7COO-

OHZn+2

2

Zinc Ricinoleate (CAS no. 13040-19-2) is the zinc salt ofRicinoleic Acid. Other names include:12-Hydroxy-9-Octadecenoic Acid, Zinc Salt and9-Octadecenoic Acid, 12-Hydroxy-, Zinc Salt

Anticaking agent,deodorant agent, andopacifying agent

CH3(CH2) 5CHCH2CH

OH

CH(CH2)7C OCH2(CH2)14CH3

O

Cetyl Ricinoleate (CAS no.10401-55-5) is the ester of cetylalcohol and Ricinoleic Acid. Other names include: Hexadecyl12-Hydroxy-9-Octadecenoate; 12-Hydroxy-9-OctadecenoicAcid, Hexadecyl Ester; 9-Octadecenoic Acid, 12-Hydroxy-,Hexadecyl Ester; and Ricinoleic Acid, Hexadecyl Ester

Skin-conditioningagent—occlusive

CH3(CH2)5CHCH2CH

OH

CH(CH2)7C

O

OCH2CH3

CH3(CH2)5CHCH2CH

OH

CH(CH2)7C

O

OCH2CH3

CH3(CH2)5CHCH2CH

OH

CH(CH2)7C

O

OCH2CH3

Ethyl Ricinoleate (CAS no. 55066-53-0) is the ester of ethylalcohol and Ricinoleic Acid. Other names include: Ethyl12-Hydroxy-9-Octadecenoate; 12-Hydroxy-9-OctadecenoicAcid-, Ethyl Ester; 9-Octadecenoic Acid, 12-Hydroxy-, EthylEster; and Ricinoleic Acid, Monoethyl Ester

Fragrance ingredientand skin-conditioningagent—emollient

C H (C H 2)5 C H 3

C H (C H 2 )7 C O C H 2 C H 2 O HC H 2 C H

O

O H Glycol Ricinoleate (CAS nos. 106-17-2 and 40275-40-9) is theester of ethylene glycol and Ricinoleic Acid. Other namesinclude: 1,2-Ethanediol Monoricinoleate; Ethylene GlycolMonoricinoleate; Glycol Monoricinoleate; 2-Hydroxyethyl12-Hydroxy-9-Octadecenoate; 9-Octadecenoic Acid,12-Hydroxy-, 2-Hydroxyethyl Ester; and Ricinoleic Acid,2-Hydroxyethyl Ester

Emulsion stabilizerand skin-conditioningagent—emollient




TABLE 1Structures, definitions, and functions of ricinoleic acid, its salts, and esters (Gottschalck and McEwen 2004) (Continued)

Structure Definition Function

CH3(CH2)5CHCH2CH

OH

CH(CH2)7C OCHCH3

O

CH3

Isopropyl Ricinoleate (CAS no. 71685-99-9) is the ester ofisopropyl alcohol and Ricinoleic Acid. Other names include:12-Hydroxy-9-Octadecenoic Acid, 1-Methylethyl Ester;1-Methylethyl, 12-Hydroxy-9-Octadecenoate; 9-OctadecenoicAcid, 12-Hydroxy-, 1-Methylethyl Ester; and Ricinoleic Acid,Isopropyl Ester

Skin-conditioningagent—emollient

CH3(CH2)5CHCH2CH CH(CH2)7C OCH3

O

OH

Methyl Ricinoleate (CAS nos. 141-24-2 and 23224-20-6) is theester of methyl alcohol and ricinoleic acid. Other names include:Castor Oil Acid, Methyl Ester; 12-Hydroxy-9-Octadecenoic Acid,Methyl Ester; Methyl Castor Oil Fatty Acid; Methyl12-Hydroxy-9-Octadecenoate; 9-Octadecenoic Acid, 12-Hydroxy-,Methyl Ester; and Ricinoleic Acid, Methyl Ester

Skin-conditioningagent—emollient

CH3(CH2)5CHCH2CH

CH(CH2)7C OCH2CH(CH2)9CH3

(CH2)7CH3

OH

O Octyldodecyl Ricinoleate (CAS nos. 79490-62-3 and 125093-27-8)is the ester of Octyldodecanol and Ricinoleic Acid. Other namesinclude: 12-Hydroxy-9-Octadecenoic Acid, 2-Octyldodecyl Ester;9-Octadecenoic Acid, 12-Hydroxy-, 2-Octyldodecyl Ester;2-Octyldodecyl 12-Hydroxy-9-Octadecenoate; and 2-OctyldodecylRicinoleate

Skin-conditioningagent—occlusive

has published the following requirements for castor oil: free fattyacids (“the free fatty acids in 10 g require for neutralization notmore than 3.5 ml of 0.10 N sodium hydroxide”) heavy metals(0.001%), hydroxyl value (between 160 and 168), iodine value(between 83 and 88), saponification value (between 176 and182), and specific gravity (between 0.957 and 0.961).

Hydrogenated Castor OilAccording to Nikitakis and McEwen (1990), Hydrogenated

Castor Oil consists primarily of glyceryl-tri-hydroxystearate.An earlier source (Binder et al. 1970) indicates that12-hydroxystearic acid is the principal constituent of Hydro-genated Castor Oil.

The National Formulary (Committee of Revision of theUnited States Pharmacopeial Convention 2004b) has publishedthe following requirements for Hydrogenated Castor Oil: freefatty acids (free fatty acids in 20 g require for neutralization notmore than 11.0 ml of 0.1 N sodium hydroxide), heavy metals(0.001%), hydroxyl value (between 154 and 162), iodine value(not more than 5), and saponification value (between 176 and182).

Methods of ProductionCastor Oil

According to Kathren et al. (1959), castor oil is extractedfrom the bean of the tropical plant, Ricinus communis, by eitherof the following two methods: (1) use of a solvent [not stated]or (2) mechanical crushing, grinding, and pressing. The formermethod is more efficient, leaving a more dessicated residue.

This residue, known as pomace, contains ricin and a separateallergen (Ratner and Gruehl 1929). Following extraction fromthe castor bean, neither of these two fractions is present in castoroil (Ordman 1955).

According to a more recent reference (Cornell University2001), ricin does not partition into the oil because of its watersolubility. Therefore, castor oil does not contain ricin, providedthat cross-contamination does not occur during its production.

Other sources indicate that castor oil is produced via the coldpressing of the seeds of Ricinus communis (Hui 1996) and bycold expression and subsequent clarification of the oil by heat(Gennaro 1990).

Hydrogenated Castor OilAccording to Nikitakis and McEwen (1990), Hydrogenated

Castor Oil is obtained by the controlled hydrogenation of pureCastor Oil. Another source (Campbell & Co. 2002) indicatesthat Hydrogenated Castor Oil (hard, brittle wax) results from theaddition of hydrogen to Castor Oil in the presence of a nickelcatalyst.

Ricinoleic AcidOne of the simplest methods for obtaining Ricinoleic Acid is

the hydrolysis of castor oil. Ricinoleic acid may then be sepa-rated from hydrolyzed castor Oil by successive additions of urea(i.e., urea complexing) (Chakravarty and Bose 1963). Accord-ing to a more recent source, Ricinoleic Acid results from thesaponification of castor oil (Lewis 1997).


CASTOR OIL 35

TABLE 2Chemical and physical properties of Castor Oil and Hydrogenated Castor Oil

Property Value Reference

Castor OilColor/Form Colorless to pale-yellow viscous liquid Lewis 2000Taste Slightly acrid National Toxicology Program (NTP) 2003Specific gravity 0.945 to 0.965 at 25◦/25◦C; 0.961 to 0.963 at

15.5◦/15.5◦CNTP 2003

Density 0.953 to 0.965 g/ml at 20◦C NTP 2003Viscosity 6 to 8 poises at 25◦C

283 cP at 37◦CNTP 2003Fredholt et al. 2000

Solubility In water (<1 mg/ml at 20◦C); in DMSO (≥100mg/ml at 20◦C);In 95% ethanol (≥ 100 mg/ml at 20◦C); inmethanol (miscible);In acetone (≥100 mg/ml at 20◦C)

NTP 2003

Miscible in absolute alcohol, glacial acetic acid,chloroform, and ether

Lewis 2000

Surface tension 39.0 dynes/cm at 20◦C; 35.2 dynes/cm at 80◦C NTP 2003Refractive index 1.4784 at 20◦C; 1.473 to 1.477 at 25◦C;

1.466 to 1.473 at 40◦CNTP 2003

Optical rotation Not less than +3.5◦ NTP 2003Flash point 229◦C (445◦F) NTP 2003Autoignition

temperature448◦C (840◦F) NTP 2003

Melting point −12◦C NTP 2003Boiling point 313◦C NTP 2003Freezing point −10◦C NTP 2003Saponification

value178 NTP 2003

Iodine value 85 NTP 2003Acid value <4 NTP 2003Reichert-Meissl

value<0.5 NTP 2003

Polenske value <0.5 NTP 2003Acetyl value 144 to 150 NTP 2003Hydroxyl value 161 to 169 NTP 2003

Hydrogenated Castor OilColor/Form White to cream waxy solid Nikitakis and McEwen 1990Odor As specified by the buyer Nikitakis and McEwen 1990

Slight characteristic odor Allegri et al. 1981Taste Tasteless Allegri et al. 1981Identification Positive: Close match to a standard IR spectrum

with no indication of foreign materialsNikitakis and McEwen 1990

Specific gravity 0.98 to 1.04 at 25◦/25◦C Nikitakis and McEwen 1990Melting range 78◦ to 90◦C Nikitakis and McEwen 1990Acid value 5.0 maximum Nikitakis and McEwen 1990Saponification

value175 to 185 Nikitakis and McEwen 1990

Iodine value As specified by the buyer Nikitakis and McEwen 1990<5.0 Budavari 1989

Hydroxyl value 155 max KIC Chemicals, Inc. 2004(Continued on next page)



TABLE 2Chemical and physical properties of Castor Oil and Hydrogenated Castor Oil (Continued)


Density 0.98 g/cm3 Physical & Theoretical Chemistry Lab 2004Solubility Insoluble in water and organic solvents. Lewis 1997

Soluble in chloroform; very slightly soluble in ben-zene; virtually insoluble in alcohol, ethyl ether, car-bon disulfide, and water

Allegri et al. 1981

Drying loss When dried under vacuum in presence of phosphoricacid anhydride, should lose no more than 0.1% ofweight

Allegri et al. 1981

Sulfuric ash Not more than 0.01% Allegri et al. 1981

Methyl RicinoleateAccording to Masri et al. (1962), Methyl Ricinoleate has

been obtained by alcoholysis of castor oil, followed by fractionaldistillation of the crude esters and further purification by lowtemperature crystallization. According to a more recent source,Methyl Ricinoleate is a product of either the esterification ofRicinoleic Acid or the alcoholysis of castor oil; the product ispurified by vacuum distillation (Lewis 1997).

Ultraviolet AbsorptionCastor Oil

A ultraviolet (UV) absorption spectrum on castor oil indicatesmaximum absorbance at 270 nm; absorption peaks at 280 and260 nm were also observed (Sasol North America, Inc. no date).

Glyceryl RicinoleateA UV absorption spectrum on Glyceryl Ricinoleate indi-

cates maximum absorbance at 270 nm and an absorption peakat 280 nm (Sasol North America, Inc. no date).

Analytical MethodsCastor Oil

Castor oil has been analyzed using the following meth-ods: mass spectroscopy (Ayorinde et al. 2000), gas-liquidchromatography (Kato and Yamaura 1970; Ramsey et al.1980), thin-layer chromatography (Srinivasulu and Mahapatra1973), and nonaqueous reverse-phase high-performance liquidchromatography–mass spectrometry (Stubiger et al. 2003).

Methyl RicinoleateMethyl Ricinoleate has been analyzed by nuclear magnetic

resonance (NMR) spectroscopy (Wineburg and Swern 1973) andgas-liquid chromatography (Paulus and Champion 1972).

ReactivityCastor Oil

Castor oil is combustible when exposed to heat, and sponta-neous heating may occur (Lewis 2000).

According to Gunstone (1989), Castor Oil is a pre-cursor of octadeca-9,11-dienoic acid (dehydration reaction);12-hydroxystearic acid (hydrogenation); heptanol and undec-10-enoic acid (pyrolysis); and sebacic acid, 10-hydroxydecanoicacid, octan-2-ol, and octan-2-one (alkaline fusion).

According to Achaya (1971), the hydrogenation of Castoroil produces 12-hydroxystearate, stearate, 12-ketostearate, andricinoleyl alcohol. Dehydrated castor oil is a dehydration productof castor oil, and contains a fair proportion of conjugated dienes.

Hydrogenated Castor OilHydrogenated Castor Oil is combustible and is incompatible

with strong oxidizing agents (Physical and Theoretical Chem-istry Lab 2004).

USE

Purpose in CosmeticsRicinus Communis (Castor) Seed Oil functions as a fra-

grance ingredient and a skin-conditioning agent—occlusive incosmetic products, and Hydrogenated Castor Oil functions as askin-conditioning agent—occlusive and a viscosity increasingagent—nonaqueous (Gottschalck and McEwen 2004). The cos-metic ingredient functions of Ricinoleic Acid and some of itssalts and esters are included in Table 1. Except for the anticaking,deodorant, and opacifying agent functions of Zinc Ricinoleateand the surfactant function of Ricinoleic Acid, Potassium Rici-noleate, Sodium Ricinoleate, Glyceryl Ricinoleate, and GlycerylRicinoleate SE, these ingredients function as skin-conditioningagents in cosmetic products. In addition to functioning as askin-conditioning agent, Ethyl Ricinoleate also functions as afragrance ingredient. Glycol Ricinoleate also functions as anemulsion stabilizer, and Glyceryl Ricinoleate and Glyceryl Ri-cinoleate SE also function as surfactants in cosmetics.

Extent of Use in CosmeticsFrequency of use data based on industry reports to the Food

and Drug Administration (FDA) in 2002 indicate that Ricinus


CASTOR OIL 37

TABLE 3Chemical and physical properties of Ricinoleic Acid, its salts, and esters


Ricinoleic AcidMolecular weight 298.47 Lide and Frederikse 1993Color/Form Yellow fatty acid Grant 1972

Yellow, viscous liquid Nikitakis and McEwen 1990Colorless to yellow, viscous liquid Lewis 1997

Odor As specified by the buyer Nikitakis and McEwen 1990Identification Positive: Close match to a standard IR spectrum with no in-

dication of foreign materialsNikitakis and McEwen 1990

Specific gravity 0.940 at 25◦/25◦C Nikitakis and McEwen 1990Density 0.9450 Lide and Frederikse 1993

0.940 at 27.4◦/4◦C Lewis 1997Solubility Insoluble in water Grant 1972

Soluble in alcohol, acetone, ether, and chloroform Budavari 1989Soluble in ethyl alcohol and diethyl ether Lide and Frederikse 1993Soluble in most organic solvents; insoluble in water Lewis 1997

Refractive index 1.4716 at 20◦C Nikitakis and McEwen 19901.4716 Lide and Frederikse 19931.4697 at 20◦C Lewis 1997

Optical rotation [α]22/D of +6.67◦C Budavari 1989+6.67◦ at 22◦C Nikitakis and McEwen 1990[α]12/Dof +5.05 Lide and Frederikse 1993Dextrorotatory Lewis 1997

Melting point 5.5◦C Nikitakis and McEwen 1990α : 7.7◦C; β: 16◦C; γ : 5.5◦C Lide and Frederikse 19935.5◦C Lewis 1997

Boiling point 226.8◦C Lide and Frederikse 1993226◦C at 10 mm Hg Lewis 1997

Combustibility Combustible Lewis 1997Neutralization value 187.98 Budavari 1989

188 Nikitakis and McEwen 1990Iodine value 85.05 Budavari 1989

85 Nikitakis and McEwen 1990

Potassium RicinoleateColor/Form White paste Lewis 1997Solubility Soluble in water Lewis 1997Combustibility Combustible Lewis 1997

Sodium RicinoleateColor/Form White or slightly yellow powder Lewis 1997Odor Nearly odorless Lewis 1997Solubility Soluble in water or alcohol Lewis 1997Combustibility Combustible Lewis 1997

Zinc RicinoleateColor/Form Fine white powder Lewis 1997Odor Faint fatty acid odor Lewis 1997Density 1.10 at 25◦/25◦C Lewis 1997




TABLE 3Chemical and physical properties of Ricinoleic Acid, its salts, and esters (Continued)


Melting point 92◦C to 95◦C Lewis 1997Combustibility Combustible Lewis 1997

Methyl RicinoleateColor/Form Colorless liquid Lewis 1997Solubility Insoluble in water; soluble in alcohol and ether Lewis 1997Density 0.9236 at 22◦/4◦C Lewis 1997Refractive index 1.4628 Lewis 1997Boiling point 245◦C at 10 mm Hg Lewis 1997Flash point −4.5◦C Lewis 1997Combustibility Combustible Lewis 1997

Ethyl RicinoleateMolecular weight 326.52 Lide and Frederikse 1993Density 0.9045 Lide and Frederikse 1993Refractive index 1.4618 Lide and Frederikse 1993Optical rotation [α]22/D of +5.3 Lide and Frederikse 1993Boiling point 258◦C Lide and Frederikse 1993

Communis (Castor) Seed Oil and Hydrogenated Castor Oil arebeing used in a total of 769 and 202 cosmetic products, respec-tively. Glyceryl Ricinoleate (16 cosmetic products), RicinoleicAcid (6 cosmetic products), Sodium Ricinoleate (12 cosmeticproducts), Zinc Ricinoleate (3 cosmetic products), and Cetyl Ri-cinoleate (55 cosmetic products) were also reported. These dataare given in Table 4 (FDA 2002).

Use concentration data obtained from an industry survey bythe Cosmetic, Toiletry, and Fragrance Association (CTFA 2004)indicate that Ricinus Communis (Castor) Seed Oil and Hydro-genated Castor Oil are being used in cosmetics at concentrationsup to 81% and 39%, respectively (see Table 4).

Other maximum ingredient use concentrations reported inTable 4 are as follows: Glyceryl Ricinoleate (up to 12%), ZincRicinoleate (up to 2%), Cetyl Ricinoleate (up to 10%), andOctyldodecyl Ricinoleate (up to 5%). Of the product categorieslisted in Table 4, the highest reported use concentration for Rici-nus Communis (Castor) Seed Oil is associated with lipsticks.Two other sources indicate that lipstick contains 44% w/wcastor oil (Hui 1996) and 10% to 67% castor oil (Smolinske1992).

Certain ingredients in this group are reportedly used in a givenproduct category, but the concentration of use is not available.For other ingredients in this group, information regarding useconcentration for specific product categories is provided, but thenumber of such products is not known. In still other cases, aningredient is not in current use, but may be used in the future.For example, Potassium Ricinoleate, Ethyl Ricinoleate, GlycolRicinoleate, Isopropyl Ricinoleate, and Methyl Ricinoleate arenot currently reported to FDA as in use, nor are there industrysurvey data indicating a current use concentration.

Cosmetic products containing Ricinus Communis (Castor)Seed Oil, Hydrogenated Castor Oil, and Ricinoleic Acid and itssalts and esters are applied to most areas of the body, and couldcome in contact with the oral, ocular, or nasal mucosae. Theseproducts may be used on a daily basis, and could be appliedfrequently over a period of several years.

Product categories for Ricinus Communis (Castor) Seed Oil,Hydrogenated Castor Oil, and salts and esters of Ricinoleic Acidinclude potential aerosol applications. Bower (1999) character-ized the typical diameter of anhydrous hair spray particles in the60- to 80-µm range (typically, <1% are below 10 µm). Pumphair sprays, in contrast, have typical particle diameters of ≥80µm. Johnsen (2004) reported that the mean particle diameter isaround 38 µm in a typical aerosol spray. In practice, he statedthat aerosols should have at least 99% of particle diameters inthe 10- to 110-µm range. For comparison, Jensen and O’Brien(1993) reported a mean aerodynamic diameter of 4.25 ± 1.5 µmfor respirable particles, which is smaller than any of the cosmeticproduct particle sizes given above.

Noncosmetic UseCastor Oil, Hydrogenated Castor Oil, and Ricinoleic Acid Saltsand Esters

According to Aplin and Eiseo (1997), castor oil is used asan industrial lubricant and as a medicinal purgative; the au-thors noted that medicinal Castor Oil does not contain ricin. Mc-Keon et al. (2000) confirmed lubricant and anti-fungal uses andadditional uses in paints, coatings, and plastics.

The following uses have been reported for Hydrogenated Cas-tor Oil (Budavari 1989): in water-repellent coatings, candles,


CASTOR OIL 39

TABLE 4Current uses and concentrations of Ricinus Communis (Castor) Seed Oil and Ricinoleic Acid and its salts and esters in cosmetics

Ingredient uses in each Use concentrationsProduct category (total no. of formulations) product category (FDA 2002) (CTFA 2004) (%)

Ricinus Communis (Castor) Seed OilBaby products

Shampoos (29) — —Lotions, oils, powders, and creams (60) 1 —Other (34) 2 —

Bath productsOils, tablets, and salts (143) 1 22Soaps and detergents (421) — 0.008Bubble baths (215) — —Capsules (2) — —Other (196) 10 —

Eye makeupEyebrow pencils (102) 10 3Eyeliners (548) 11 4–8Eye shadow (576) 9 2–5Eye lotions (25) — —Eye makeup remover (100) 1 —Mascara (195) 16 0.4–3Other (152) 11 13

Fragrance productsColognes and toilet waters (684) — 0.1Perfumes (235) — 0.3–1Powders (273) — —Sachets (28) — —Other (173) — —

Noncoloring hair care productsConditioners (651) 20 0.0002–5Sprays/aerosol fixatives (275) 1 —Straighteners (63) — —Permanent waves (207) — —Rinses (42) 5 19Shampoos (884) — 0.005Tonics, dressings, etc. (598) 34 0.005–52Wave sets (53) — 16Other (277) 6 —

Hair—coloring productsDyes and colors (1690) 27 2Tints (49) — —Rinses (20) — 0.0005Shampoos (32) — —Color sprays (5) — —Lighteners with color (5) — —Bleaches (120) 1 0.04Other (55) — —

MakeupBlushers (245) 10 0.08–45Face powders (305) 1 1





(Continued)


Foundations (324) 5 0.05–6Leg and body paints (4) — —Lipsticks (962) 492 15–81Makeup bases (141) 4 0.002–20Rouges (28) 1 38–48Makeup fixatives (20) — —Other (201) 25 40–49

Nail care productsBasecoats and undercoats (44) — —Cuticle softeners (19) 1 —Creams and lotions (15) 1 —Nail extenders (1) — —Nail polishes and enamels (123) — 69Nail polish and enamel removers (36) 8 —Other (55) 3 —

Personal hygiene productsBath soaps and detergents (421) 18 ≤ 0.008Underarm deodorants (247) — 0.01–3Douches (5) — —Feminine deodorants (4) — —Other (308) 1 0.003

Shaving productsAftershave lotions (231) 2 0.004–0.03Beard softeners (0) — —Mens talcum (7) — —Preshave lotions (14) — —Shaving creams (134) — —Shaving soaps (2) — —Other (63) 1 0.03

Skin care productsSkin cleansing creams, lotions, liquids, and pads (775) 4 0.004Depilatories (34) 2 —Face and neck creams, lotions, powders, and sprays (310) 1 1–7Body and hand creams, lotions, powders, and sprays (840) 3 0.02–55Body and hand sprays — 0.004Foot powders and sprays (35) — —Moisturizers (905) 8 7Night creams, lotions, powders, and sprays (200) — 0.00004Paste masks/mud packs (271) 2 —Skin fresheners (184) — —Other (725) 8 —

Suntan productsSuntan gels, creams, liquids, and sprays (131) 1 6Indoor tanning preparations (71) — —Other (38) 1 10

Total uses/ranges for Ricinus Communis (Castor) Seed Oil 769 0.00004–81


CASTOR OIL 41


(Continued)


Hydrogenated Castor OilBaby products

Other (34) — 5Bath products

Oils, tablets, and salts (143) 1 19Soaps and detergents (421) 1 0.0003–0.7Bubble baths (215) — 4Other (196) — 3

Eye makeupEyebrow pencils (102) 11 4–26Eyeliners (548) 25 3–39Eye shadow (576) 6 2–19Eye lotions (25) — 0.5

Eye makeupEye makeup remover (100) 1 7Mascara (195) — 5Other (152) 14 22–39

Fragrance productsColognes and toilet waters (684) — 0.0003Perfumes (235) — 5Other (173) — 7

Noncoloring hair care productsShampoos (884) — 0.02Tonics, dressings, etc. (598) — 3Other (277) 1 —

MakeupBlushers (245) 2 3Foundations (324) 4 0.9–5Leg and body paints (4) — 1Lipsticks (962) 20 0.5–33Makeup fixatives (20) — 3–7Other (201) 24 0.04–13

Nail care productsCreams and lotions (15) 1 —

Oral hygiene productsOther (6) — 1–5

Personal hygiene productsUnderarm deodorants (247) 2 2–8Feminine deodorants (4) — 2Other (308) 65 —

Shaving productsAftershave lotions (231) 2 —

Skin care productsSkin cleansing creams, lotions, liquids, and pads (775) 3 1Face and neck creams, lotions, powders, and sprays (310) — 1–2Body and hand creams, lotions, powders, and sprays (840) 3 0.0003–1Foot powders and sprays (35) — 8





(Continued)


Moisturizers (905) 3 1–5Night creams, lotions, powders, and sprays (200) 1 1–3Other (725) 9 0.1–1

Suntan productsSuntan gels, creams, liquids, and sprays (131) 1 0.8–3Other (38) 2 —

Total uses/ranges for Hydrogenated Castor Oil 202 0.0003–39

Glyceryl RicinoleateEyebrow pencil (102) — 11Eyeliner (548) 1 2Eyeshadow (576) 5 —Other eye makeup products (152) 1 2–12Lipsticks (962) 5 —Other shaving products (63) 1 —Body and hand creams, lotions, powders, and sprays (840) 2 —Night creams, lotions, powders, and sprays (200) 1 —

Total uses/ranges for Glyceryl Ricinoleate 16 12

Ricinoleic AcidBath preparations

Oils, tablets and salts (143) 1 —Fragrance preparations

Colognes and toilet waters (684) 1 —Other fragrance preparations (173) 4 —

Total uses/ranges for Ricinoleic Acid 6 —

Sodium RicinoleateBaby products

Other baby products (34) 1 —Bath Preparations

Soaps and detergents (421) 10 —Noncoloring Hair Preparations

Shampoos (884) 1 —Total uses/ranges for Sodium Ricinoleate 12 —

Zinc RicinoleateNoncoloring hair preparations

Hair sprays/aerosol fixatives (275) — 1Personal hygiene products

Underarm deodorants (247) 2 2Skin care preparations

Skin cleansing creams, lotions, liquids, and pads (775) 1 —Body and hand skin care preparations (sprays) (840) — 1

Total uses/ranges for Zinc Ricinoleate 3 1–2

Cetyl RicinoleateMakeup preparations

Blushers (245) — 3


CASTOR OIL 43


(Continued)


Foundations (324) 3 2–3Lipsticks (962) 26 0.5–10Other makeup preparations (201) 1 —

Skin care preparationsSkin cleansing creams, lotions, liquids, and pads (775) 2 0.1–0.5Body and hand skin care preparations (840) 1 —Moisturizers (905) 15 0.1–2Paste masks (mud packs) (271) 3 —Other skin care preparations (725) 3 4

Suntan preparationsOther suntan preparations (38) 1 —

Total uses/ranges for Cetyl Ricinoleate 55 0.1–10

Octyldodecyl RicinoleateFragrance preparations

Other fragrance preparations (173) — 3Makeup preparations

Lipsticks (962) — 3–5Total uses/ranges for Octyldodecyl Ricinoleate — 3–5

shoe polish, carbon paper, and ointments; for impregnating pa-per, wood, and cloth; for electrical condenser impregnation; asa solid lubricant; and as a pressure mold release agent in themanufacture of formed plastics and rubber goods. The use ofHydrogenated Castor Oil in waterproofing fabrics has also beenreported (Lewis 1997).

According to FDA’s OTC (Over-the-Counter) Drug ReviewIngredient Status Report (FDA 2003a), castor oil is classifiedas generally recognized as safe and effective for use as a stimu-lant laxative, but not generally recognized as safe and effectivefor use as a wart remover. For use as a stimulant laxative, thesingle daily dose reported for one product ranges from 15 to60 ml for adults and children ≥12 years (Drugstore.com, Inc.2004).

FDA had issued a proposed rule in 1982 stating that Castor oilis generally recognized as safe and effective and not misbrandedwhen used as an active ingredient (laxative) in OTC laxative drugproducts (FDA 1985) and a final rule is pending (FDA 2003a).FDA has concluded that castor oil does not meet monographconditions and is not generally recognized as safe and effectivefor use as a wart remover in OTC wart remover drug products(FDA 1990).

Castor oil is included in the list of inactive ingredients (ex-cipients) present in approved oral, intramuscular, and topicaldrug products or conditionally approved drug products that arecurrently marketed for human use (FDA 2003b).

FDA-approved direct/indirect food additive uses of Castoroil and the following Ricinoleic Acid salts and esters are sum-marized in Table 5: Potassium Ricinoleate, Sodium Ricinoleate,Zinc Ricinoleate, Glycol Ricinoleate, Isopropyl Ricinoleate, andMethyl Ricinoleate.

The Joint Food and Agriculture Organization (FAO)/WorldHealth Organization (WHO) Expert Committee on Food Addi-tives (1980) established an acceptable daily intake (for man) of0 to 0.7 mg/kg body weight for castor oil. The determinationof range was based on consideration of the lack of adequatelong-term studies.

Ricinoleic AcidNoncosmetic uses of Ricinoleic Acid are as follows: turkey

red oil, textile finishing, source of sebacic acid and heptanol,ricinoleate salts, and 12-hydroxystearic acid (Lewis 1997).

Zinc RicinoleateThe following noncosmetic uses of Zinc Ricinoleate have

been reported: fungicide, emulsifier, greases, lubricants, water-proofing, lubricating-oil additive, and stabilizer in vinyl com-pounds (Lewis 1997).

Methyl RicinoleateNoncosmetic uses of Methyl Ricinoleate include: plasticizer,

lubricant, cutting oil additive, and wetting agent (Lewis 1997).



TABLE 5Direct/indirect food additive uses of Castor Oil, Hydrogenated Castor Oil, and Ricinoleic acid salts and esters

Code of FederalUse Specification/listing Regulations (CFR)

Diluent Not more than 500 ppm Castor Oil in the finished food maybe used safely as a diluent in color additive mixtures forfood use that are exempt from certification.

21 CFR 73.1

Release/antisticking agent Provided that Castor Oil meets the specifications of theUnited States Pharmacopeia, it is permitted for use as arelease agent and antisticking agent, not to exceed 500ppm in hard candy.

21 CFR 172.876

Natural flavoring substanceand adjuvant

Castor Oil is included in the list of natural flavoringsubstances and natural adjuvants that are permitted fordirect addition to food for human consumption.

21 CFR 172.510

Plasticizer Castor Oil is approved for use as a plasticizer (total not toexceed 30% by weight of rubber product, unless otherwisespecified) in rubber articles that have been declared safefor use in producing, manufacturing, packing, processing,preparing, treating, packaging, transporting, or holdingfood.

21 CFR 177.2600

Component of food-contactsurface

Hydrogenated Castor Oil may be used safely as acomponent of the uncoated or coated food-contact surfaceof paper and paperboard intended for use in producing,manufacturing, packaging, processing, preparing, treating,packing, transporting, or holding aqueous and fatty foods.

21CFR176.170

Component of food-contactsurface

Hydrogenated Castor Oil may be used safely as acomponent of the uncoated or coated food-contact surfaceof paper and paperboard intended for use in producing,manufacturing, packaging, processing, preparing, treating,packing, transporting, or holding dry food.

21CFR176.180

Component of defoamingagents

Castor Oil, Hydrogenated Castor Oil, Glycol Ricinoleate,Isopropyl Ricinoleate, and Methyl Ricinoleate are amongthe substances that are permitted for use in the formulationof defoaming agents that have been declared safe for usein the manufacture of paper and paperboard intended foruse in packaging, transporting, or holding food.

21 CFR 176.210

Component of surfacelubricants

Castor Oil is included in the list of substances permitted foruse in surface lubricants that have been declared safe foruse in the manufacture of metallic articles that contactfood. May be used in surface lubricants employed tofacilitate the drawing, stamping, or forming of metallicarticles from rolled foil or sheet stock by furtherprocessing, provided that the total residual lubricantremaining in the metallic article in the form in which itcontacts food does not exceed 0.2 mg per square inch offood-contact surface.

21 CFR 178.3910

Component of cellophane Hydrogenated Castor Oil is included in the list ofcomponents of cellophane that may be safely used forpackaging food.

21CFR 177.1200


CASTOR OIL 45

TABLE 5Direct/indirect food additive uses of Castor Oil, Hydrogenated Castor Oil, and Ricinoleic acid salts and esters (Continued)

Code of FederalUse Specification/listing Regulations (CFR)

Component ofclosure-sealing gaskets

Hydrogenated Castor Oil may be employed in themanufacture of closure-sealing gaskets that may be safelyused on containers intended for use in producing,manufacturing, packing, processing, preparing, treating,packaging, transporting, or holding food.

21CFR177.1210

Component of cross-linkedpolyester resins

Hydrogenated Castor Oil may be used in the production ofor may be added to cross-linked polyester resins that maybe safely used as articles or components of articles that areintended for repeated use in contact with food.

21CFR 177.2420

Textiles and textile fibercomponents derived fromCastor Oil

Fats, oils, fatty acids, and fatty alcohols derived from CastorOil are included in the list of substances that are permittedfor use in textiles and textile fibers that have been declaredsafe for use as articles or components of articles that areintended for use in producing, manufacturing, packing,processing, preparing, treating, packaging, transporting, orholding food.

21 CFR 177.2800

Component of adhesives Polymeric esters of polyhydric alcohols and polycarboxylicacids prepared from glycerin and phthalic anhydride andmodified with Castor Oil are permitted for use inadhesives that have been declared safe for use ascomponents of articles intended for use in packaging,transporting, or holding food. Methyl Ricinoleate is alsopermitted for use in these adhesives.

21 CFR 175.105

Component of resinous andpolymeric coatings

Castor Oil, Hydrogenated Castor Oil, PotassiumRicinoleate, Sodium Ricinoleate, and Zinc Ricinoleate areincluded in the list of substances employed in theproduction of resinous and polymeric coatings that havebeen declared safe for use as the food-contact surface ofarticles intended for use in producing, manufacturing,packing, processing, preparing, treating, packaging,transporting, or holding food.

21 CFR 175.300

BIOLOGICAL PROPERTIES

Absorption, Distribution, Metabolism, and ExcretionCastor Oil

In a study by Paul and McKay (1942), two rabbits (weight= 3 kg) were fed 6% castor oil in the diet for 18 days; fecalcollection occurred during the last ten days. The utilization (un-corrected for metabolic fat) of castor oil was 92.1%, which theauthors considered to be efficient utilization. For both rabbits,the percentage of fat in the feces was 2.2%.

In a study by Stewart and Sinclair (1945), adult rats (number,weights, and strain not stated) received a diet containing 48.4%castor oil for 4 to 6 weeks. Control rats received stock rationonly. Feces were collected from three rats on the castor oil diet.At the end of the feeding period, excised organs/tissues wereground thoroughly and samples of phospholipid fatty acids were

obtained from the liver, small intestine, and muscle; glyceridefatty acids were obtained from the liver and fat depots. Therewas no evidence of catharsis in any of the animals.

Average percentages of Ricinoleic Acid in the phospholipidfatty acids were as follows: liver (test: 1.3 ± 0.6% [9 analy-ses]; controls: 1.7 ± 1.1% [7 analyses]), small intestine (test:4.9 ± 1.7% [8 analyses]; controls: 6.0 ± 4.4% [4 analyses]),and skeletal muscle (test: 3.6 ± 2.9% [8 analyses]; controls:4.0 ± 1.7% [7 analyses]). The following values are averagepercentages of Ricinoleic Acid in glycerides and cholesterol es-ters: fat depots (test: 6.8 ± 4.2% [11 analyses]; controls: 0.5 ±0.5% [7 analyses]) and liver (test: 7.2 ± 2.4% [8 analyses]; con-trols: 5.6 ± 4.1% [5 analyses]).

The authors concluded that the feeding of castor oil did notlead to the appearance of significant amounts of Ricinoleic Acidin phospholipids of the small intestine, liver, and skeletal muscle,



nor in glycerides of the liver. Additionally, they concluded thatricinoleic acid is a component acid of the glycerides in the fatdepots, comprising 7% of the total fatty acids. The fatty acidsexcreted by each of three rats amounted to 2.1%, 2.2%, and3.6% of those ingested. Total body fat in these three animalswas also determined, and it was calculated that 1% to 2% ofabsorbed Ricinoleic Acid was deposited in the fat depots. Theauthors concluded that Ricinoleic Acid was rapidly metabolized(Stewart and Sinclair 1945).

Watson and Gordon (1962) studied the digestion, absorption,and metabolism of castor oil (medicinal grade) in eight maleSprague-Dawley rats (weights = 100 to 200 g). The compositionof the castor oil was as follows: ricinoleic acid (90.0%), linoleicacid (4.7%), oleic acid (3.2%), stearic acid (1.0%), palmitic acid(1.0%), and palmitoleic acid (0.1%). In the first experiment, fourrats were fed rat chow ad libitum, and the remaining four werefasted overnight. On the following morning, castor oil (1.0 ml)was dosed via stomach tube and chyle was collected over a 24-h period. The mean values for percent recovery of RicinoleicAcid in fasted and fed rats were 6.8% and 24.2%, respectively(p < .01).

In the second experiment, seven weanling rats were fed a dietconsisting of rat chow that had been mixed with castor oil (20%by weight). The control group was fed an olive oil-supplementeddiet. After 4 and 8 weeks of feeding, an epididymal fat pad wasremoved from each rat in both groups, and fatty acid compositionwas determined using gas-liquid chromatography. Mean valuesfor Ricinoleic Acid in the fat pad after 4 and 8 weeks of feedingwere 9.1±1.7 and 9.7±1.0%, respectively. Ricinoleic Acid wasundetectable in the fat pads of control rats fed olive oil. For ratsfed castor oil, random analyses of feces indicated a considerablefraction of hydroxystearic acid. However, hydroxystearic acidwas undetectable in the feces of rats fed a normal diet. Theauthors suggested that hydrogenation of Ricinoleic Acid in thegut lumen by intestinal bacteria would be a likely explanationfor this finding.

The relationship between dose and absorption of castor oilwas studied in the final experiment. Polyethylene cannulae wereinserted into the thoracic duct and duodenum of each of tworats, and the animals received 0.5 N saline overnight. On thefollowing morning, one rat received 0.2 ml and one rat received0.6 ml of castor oil, and the rats were killed 45 min post dos-ing. Only the high dose induced diarrhea. Intestines (small andlarge) were excised, homogenized, and tissue lipids were ex-tracted. Chyle was also collected and extracted. Total lipid esti-mation and gas-liquid chromatography (GLC) analysis of fattyacids were performed on the extracts. For the rat dosed with 0.2ml castor oil, the percentage of Ricinoleic Acid in the chyle was18.1% and the percentage detected in the small bowel lipids was6.2%. For the rat dosed with 0.6 ml Castor Oil, the percentageof Ricinoleic Acid in the chyle was 3.0% and the percentage inthe small bowel was 3.1%. Ricinoleic Acid was undetectable inlarge bowel lipids from the rat with diarrhea. The result indicatesa close correlation between the dose administered and the per-

centage of Ricinoleic Acid in the feces, i.e., greater absorptionat the lower dose (Watson and Gordon 1962).

Castor oil is metabolized to Ricinoleic Acid by pancreaticlipase in hamsters (Gaginella and Bass 1978). Thompson (1980)reported that Castor Oil is a triglyceride that is hydrolyzed inthe small intestine in humans by pancreatic enzymes, leading tothe release of glycerol and Ricinoleic Acid.

In a study by Hagenfeldt et al. (1986), castor oil was ad-ministered intragastrically to germ-free and conventional rats(number not stated). Urine was collected at intervals over a24-h period. The following epoxydicarboxylic acids were de-tected in the urine of both germ-free and conventional rats:3,6-epoxyoctanedioic acid; 3,6-epoxydecanedioic acid; and 3,6-epoxydodecanedioic acid. These acids were not detected in urinecollected from the rats prior to dosing with castor oil, and theyalso were not detected in steam-sterilized castor oil. The authorsstated that results for the germ-free rat indicate that the cycliza-tion of Ricinoleic Acid (hydroxy fatty acid in castor oil) to forman epoxy compound occurs endogenously and does not requirethe presence of intestinal bacteria.

In a study by Ihara-Watanabe et al. (1999), two groups of fivemale Wistar rats (3 weeks old) received 10% castor oil in thediet (cholesterol-enriched and cholesterol-free, respectively) for20 days. In both dietary groups, a very small quantity of Rici-noleic Acid was present in perirenal adipose tissue, but not inthe serum or hepatic tissue. It was also noted that the perirenalfatty acid profiles did not reflect those of the dietary fats, eitherin the absence or presence of dietary cholesterol. The fecal re-covery of Ricinoleic Acid was approximately 0.5% of the totalingested. It was concluded that castor oil was readily absorbedand metabolized.

Hydrogenated Castor OilIn a study by Binder et al. (1970), groups of 15 male albino

rats (Slonaker substrain of Wistar strain, weights = 43 to 83 g)received diets containing the following oils: group 1 (fed 1%Hydrogenated Castor Oil (HCO) + 19% corn oil for 16 weeks),group 2 (1% HCO + 19% corn oil for 8 weeks, then 20% corn oilfor 8 weeks), group 3 (10% HCO + 10% corn oil for 16 weeks),and group 4 (10% HCO + 10% corn oil for 8 weeks, then 20%corn oil for 8 weeks). The control group received 20% corn oil inthe diet for 16 weeks. The sample of HCO that was incorporatedinto the diet contained 86.5% 12-hydroxystearic acid, 10.3%nonoxygenated acids, and 3.2% 12-ketostearic acid. Thus, theeffective dietary concentrations of Hydrogenated Castor Oil inthe 1% and 10% diets were 0.865% and 8.65%, respectively.Results relating to the toxicity of HCO are summarized in thesection Subchronic Oral Toxicity later in the report.

After 4 weeks of feeding, some of the animals on the 1% HCO(three rats) and 10% HCO (three rats) diets were necropsied andexcised abdominal adipose tissue from each group was pooled.At weeks 4 and 8, sets of three rats on the corn oil diet were used.At the end of the 16-week feeding period, adipose tissue fromrats in the various dietary groups was analyzed. Adipose tissue


CASTOR OIL 47

was not pooled. After 8, 12, and 16 weeks, lipids were extractedfrom three rats on each diet. Methyl esters were recovered fromthe extracted lipids and chromatographed.

The deposition of hydroxystearic acid in abdominal fatand other body lipids was reported. In all cases, it wasaccompanied by hydroxypalmitic acid, hydroxymyristic acid,and hydroxylauric acid (hydroxy-stearic acid metabolites).The percent composition of these HCO-derived hydroxy fattyacids in rat lipids was as follows: 12-hydroxystearic acid(≈81%), 10-hydroxypalmitic acid (≈17%), 8-hydroxymyristicacid (≈1.6%), and 6-hydroxylauric acid (≈0.4%). After 4 weekson the 1% HCO diet, HCO-derived fatty acids accounted for0.90% (by weight) of the abdominal fat fatty acids. This propor-tion decreased to ≈0.35% over the 8- to 16-week feeding period.Compared to the abdominal fatty acids, the acids obtained fromthe carcass lipids contained a smaller proportion of HCO-derivedhydroxyacids (≈0.28% over the 8- to 16-week feeding period).The period encompassing 4 weeks of feeding on the 10% HCOdiet yielded the greatest content of HCO-derived hydroxy acidsin the lipids (i.e., 4.4% hydroxy acids in abdominal fat). At 16weeks, this proportion had decreased to <2% (about same as inthe carcass lipids).

A rapid decrease in the amount of HCO-derived hydroxy fattyacids in the tissues was noted when the HCO diet was changedto the control diet (Binder et al. 1970).

Ricinoleic Acid and Methyl RicinoleateUchiyama et al. (1963) studied the accumulation of hydroxy

acids in depot fat after rats were fed with Ricinoleic Acid intwo experiments. In the first experiment, adult male rats (num-ber, strain, and weights not stated) were fed Ricinoleic Acid(5% emulsion, 20 ml) for 7 days. In the second experiment, theanimals were fed for 27 days. Lipid extraction from the fat tis-sue was followed by hydrolysis to yield a fatty acid mixture. Agas-liquid chromatogram indicated appreciable amounts of thefollowing hydroxy fatty acids with shorter chain lengths thanRicinoleic Acid: 10-hydroxyhexadecenoic acid (experiment 1:0.60% of total fatty acids; experiment 2: 0.33% of total fattyacids), 8-hydroxytetradecenoic acid (experiment 1: 0.03% oftotal fatty acids; experiment 2: 0.08% of total fatty acids), and6-hydroxydodecenoic acid (experiment 2: 0.03% of total fattyacids). Ricinoleic Acid comprised 0.51% of total fatty acids inexperiment 1 and 3.85% of total fatty acids in experiment 2.

In a study by Okui et al. (1964), the metabolism of hy-droxy fatty acids was evaluated using male albino rats (weight= 120 ± 10 g). The rats received 1.5 g Ricinoleic Acid or anemulsion containing 5% (w/v) Ricinoleic Acid by stomach tubethree times per day for a desired period. Feces were collectedevery 24 h until the animals were killed. The animals were killed20 h after the last dose, and subcutaneous adipose tissue was re-moved for analyses. Oral dosing with Ricinoleic Acid resultedin a fecal excretion rate (for Ricinoleic Acid) ranging from 1%to 4%. Following oral administration for up to 30 days, the ac-

cumulation of hydroxy acids by 5% of fatty acids in fat tissuewas noted. Analyses of adipose tissue indicated an occurrenceof shorter chain hydroxy acids other than Ricinoleic Acid.

Ricinoleic Acid was also injected intraperitoneally to deter-mine whether another route of administration would lead to theformation of shorter chain hydroxy acids. After Ricinoleic Acidwas injected intraperitoneally daily for 7 days, Ricinoleic Acidaccumulated in the adipose tissue; no shorter chain hydroxyacids were reported (Okui et al. 1964).

In a study by Rao et al. (1969), Ricinoleic Acid or MethylRicinoleate was administered via gastric intubation to male rats(minimum weight of 400 g) with a cannulated thoracic duct.Lymph was collected for 48 h, and the lipids were then ex-tracted and separated into various lipid classes. Results indicatedthat Ricinoleic Acid was present in the triglyceride, diglyceride,monoglyceride, and free fatty acid fractions. Peak absorption ofRicinoleic Acid occurrred within 30 min post administration. Ri-cinoleic Acid was not present in the phospholipid or cholesterolester fractions of the lymph lipids.

Percutaneous AbsorptionRicinoleic Acid

Butcher (1952) evaluated the skin penetration of RicinoleicAcid in vivo using rats that were 20 to 30 days old. In order toincrease the fluorescence of Ricinoleic Acid, either one part ofmethyl anthranilate or methylcholanthrene was added to 99 partsRicinoleic Acid. The test substance was either gently rubbedon to skin that had been clipped free of hair. Biopsies weretaken at various intervals post application. The preparations wereobserved using a Spencer microscope with a quartz condenser.Ricinoleic Acid was retained mainly in the outer strata of theepidermis. There was little evidence of deeper penetration inbiopsies that were taken at 2 h post application.

In a study by Baynes and Riviere (2004), the percutaneous ab-sorption of a radiolabeled [3H]Ricinoleic Acid (specific activity= 20.0 mCi/mmol) mixture was evaluated using porcine skinmembranes or silastic (polydimethylsioloxane) membranes inthe Bronaugh flow-through diffusion cell system. [3H]RicinoleicAcid (5%) mixtures were prepared in water containing either5% mineral oil or 5% PEG 200. Other [3H]Ricinoleic Acidmixtures were formulated with the following three commonlyused cutting fluid additives: triazine, linear alkylbenzene sul-fonate, and triethanolamine. At 8 h after topical exposure, Ri-cinoleic Acid absorption (based on amount recovered in re-ceptor fluid) ranged from 1% to 13% in silastic membranesand 0.1% to 0.3% in porcine skin membranes. For most mix-tures, peak absorption of Ricinoleic Acid occurred within 3h. The greatest Ricinoleic Acid peak concentrations were as-sociated with the control mixtures containing PEG in bothmembranes.

At the conclusion of the 8-h perfusion experiments, as muchas 5% of the dose of Ricinoleic Acid was detected in the dosedskin, and as much as 16% of the dose was detected in the stratum



corneum with mineral oil formulations. With polyethylene gly-col (PEG) formulations, the amount of Ricinoleic Acid remain-ing in the skin tissues was considerably less. The cutting fluidadditives significantly decreased Ricinoleic Acid partitioningfrom the formulation into the stratum corneum in PEG-basedmixtures. Additionally, the individual additives or combinationsof these additives significantly reduced Ricinoleic Acid per-meability in silastic membranes and porcine skin (Baynes andRiviere 2004).

Skin Penetration EnhancementRicinoleic Acid

In a study by Song et al. (2001), the effects of cis-9-octadecenoic acid (oleic acid) and a group of chemically re-lated cis- (Ricinoleic Acid) and trans- (ricinelaidic acid) 12-monohydroxylated derivatives and their ethyl and methyl esterson the skin penetration of model hydrophobic (hydrocortisone)and hydrophilic (5-fluorouracil) drugs were evaluated in vitro us-ing hairless mouse skin. Test solutions were prepared by placingeither test compound (5-fluorouracil, 5.4 mg; hydrocortisone,15 mg) with or without an unsaturated fatty acid (50 mg each)or fatty acid ester (50 mg each) in a screw-capped glass vial,and adding propylene glycol (final volume = 1 ml). The mix-ture was sonicated to effect complete dissolution. Permeationstudies were conducted using Vlia-Chien diffusion cells andfull thickness abdominal skin from female hairless HRS/J mice(6 weeks old). Ricinoleic Acid enhanced the in vitro transdermalpermeation of 5-fluorouracil.

The transdermal penetration rate of hydroquinone frompropylene glycol was very slow. However, in the presence ofoleic acid, the penetration rate accelerated and was enhancedapproximately 1800-fold. In the presence of Ricinoleic Acid,the enhancement of hydroquinone skin penetration was less than1.5-fold. Regarding the penetration of 5-flurouracil, fluxes weremuch higher in the presence of oleic acid (333-fold increase;p < .001) than in the presence of Ricinoleic Acid (<5-foldincrease) (Song et al. 2001).

Transepidermal Water LossCastor Oil

Lieb et al. (1988) evaluated transepidermal water loss(TEWL) using a modification of a flow-through diffusioncell that was originally designed by Bronaugh and Stew-art (1985). The membrane was described as full-thickness,cartilage-stripped skin obtained from the ventral ear of the maleSyrian golden hamster. Castor oil (10 µl) was placed on the skin(0.32-cm2 area), and a TEWL rate–versus-time study was con-ducted. Tritiated water (HTO) permeated through the membraneinto the diffusion cell’s receptor compartment. Flux (TEWL,µg/cm2/h) was determined (using a scintillation counter) bymeasuring the HTO that adsorbed to anhydrous calcium chlo-ride in the receptor cell. Castor oil caused a marked decrease inthe TEWL rate. For untreated skin, the mean TEWL rate was

approximately 450 µg/cm2/h at 1 h. Mean values for the TEWLrate were approximately 400 µg/cm2/h at 1 h and 250 µg/cm2/hat 24 h. Additionally, castor oil was the only substance that ex-hibited a burst effect, i.e., initially, the membrane became fullyhydrated and swollen and was more permeable, providing an“increased push” effect to pass water through the membranetoward the anhydrous desiccant.

Effect on Smooth MuscleCastor Oil and Ricinoleic Acid

Mathias et al. (1978) evaluated the effect of Castor Oil andRicinoleic Acid on smooth muscle of the rabbit small intes-tine. Anesthetized male New Zealand white rabbits (weightsbetween 1.5 and 3.0 kg) were used in ileal loop studies. Cas-tor oil (dose = 0.85 ml/kg) was administered into the orad endof the ileal loop, and myoelectric recording techniques wereused. Ricinoleic Acid was administered by intraluminal infusion(2 µg/kg/min [6 mM] into the orad end). The term migratingaction potential complex (MAPC) was used to describe the my-oelectric activity that has been observed in certain abnormalstates. MAPC has been defined as action potential discharge ac-tivity occurring for longer than 2.5 s, on at least two consecutiveelectrode sites at 2.5-cm intervals, and having a propagation ve-locity of ∼=1.0 cm/s. The myoelectric activity of castor oil andRicinoleic Acid was similar to the MAPC that was observedin the cholera enterotoxin-infected loops. Castor oil induced analteration in myoelectric activity.

In experiments that were designed to study the motor re-sponse in segments of the duodenum, mid-jejunum, terminalileum, and sigmoid colon (four experiments, respectively), Ri-cinoleic Acid was diluted with 0.9% sodium chloride solution toa volume that would deliver 1.14 ml/h. No MAPC activity wasobserved in control experiments in which 0.9% sodium chloridesolution was perfused into the duodenum at a rate of 1.14 ml/h.When compared to control values, there was no statistically sig-nificant difference in the slow wave frequency or slow wavepropagation velocity in loops exposed to castor oil or RicinoleicAcid (Mathias et al. 1978).

Lodge (1994) evaluated the potential for Ricinoleic Acid toinduce vasoconstriction using tissues from male New Zealandwhite rabbits. After removal of the thoracic aorta and left andright external jugular veins, the vessels were cleaned and cutinto rings. Following removal of the endothelium, the ringswere suspended between two wire holders in tissue baths. Ri-cinoleic Acid was diluted with ethanol to produce final bathconcentrations ranging from 0.1 to 30 µg/ml (molar concen-tration range of 0.335 to 100.50 µM). Ricinoleic Acid in-duced vasoconstriction (EC50 = 0.24 ± 0.04 µg/ml) that wasconcentration-dependent and sensitive to the inhibitory effectof ifetroban, but not indomethacin. Ricinoleic acid also evokedconcentration-dependent force development (constriction) in theaorta (EC50 = 4.7 ± 0.7 µg/ml), and this response was antago-nized by ifetroban.


CASTOR OIL 49

Sodium Ricinoleate, Castor Oil, and Ricinoleic AcidStewart and Bass (1976a) evaluated the effects Sodium Rici-

noleate, castor oil, and Ricinoleic Acid on the digestive contrac-tility of the canine small bowel using four male, mixed breeddogs (weights between 10 and 15 g). After feeding, each animalreceived a single bolus infusion of Sodium Ricinoleate (500 mgin 30 ml of saline) into the duodenum. Saline (30-ml volume)served as the control. A duodenal cannula was implanted in eachanimal, and circular muscle activity was recorded for 1 h. Eachanimal was dosed with Sodium Ricinoleate in two experiments,and with isotonic saline (30 ml) in two control experiments. Inadditional experiments, alterations in digestive contractile pat-terns were monitored after administration (gastric tube) of castoroil or Ricinoleic Acid (volume= 10 ml) one h after feeding. Eachtreatment was repeated twice in each of two animals.

Intraduodenal administration of Sodium Ricinoleate pro-duced a biphasic response in the proximal and mid-jejunum con-sisting of brief initial stimulation, followed by inhibition of di-gestive contractility. Compared to the control experiments, thesestimulatory and inhibitory effects on intestinal contractility weredescribed as significant (p < .05) changes in the average forceper contraction. The changes in mid-jejunal digestive contrac-tility were similar to those observed in the proximal jejunum.

The oral administration of Ricinoleic Acid (10 ml) inducedalterations in digestive patterns that were qualitatively similarto those induced by the intraduodenal administration of SodiumRicinoleate. Brief initial stimulation, followed by an apparentdepression of intestinal contractility, was observed after oraldosing with Castor Oil (10 ml) (Stewart and Bass 1976a).

Sodium Ricinoleate and Methyl RicinoleateIn a study by Stewart et al. (1975), Sodium Ricinoleate de-

pressed the smooth muscle twitch response of the electricallydriven guinea-pig ileum preparation at concentrations rangingfrom 1.25 × 10−5 to 4 × 10−4 M. Methyl Ricinoleate failed todepress the smooth muscle twitch response over this range of testconcentrations. Similar results were reported for spontaneouslycontracting rabbit jejunum.

Antinociceptive ActivityRicinoleic Acid and Potassium Ricinoleate

Vieira et al. (2000) evaluated the antinociceptive activity ofRicinoleic Acid (in peanut oil), dissolved in a vehicle contain-ing 10% ethanol, 10% Tween 80, and 80% saline, using groupsof 5 male albino Dunkin-Hartley guinea pigs (weights = 250to 350 g) and groups of 8 to 10 male Swiss mice (weights =20 to 25 g). A series of experiments was performed. In the firstexperiment, a single topical application of Ricinoleic Acid (900µg/mouse) was made to the ventral surface of the right paw ofeach mouse. Test substance application was followed by intra-plantar injection with carrageenan (to induce edema) 30 minlater. Ricinoleic acid significantly reduced the reaction time toa heat stimulus, compared to treatment with the vehicle. When

intraplantar injection with carageenan was preceded by repeated(8 days) topical applications of Ricinoleic Acid (900 µg/mouse),again, a marked prolongation of paw withdrawal latency to heat,compared to the vehicle control group, was noted.

Another experiment involved the repeated local application (8days) of Ricinoleic Acid (900 µg/mouse) or the repeated (4 days)intradermal injection of Potassium Ricinoleate (30 µg/mouse)on the ventral surface of the right paw. Freund’s adjuvant hadbeen injected into the hindpaw on the first day. The paw with-drawal latency to a painful stimulus (heat) after topical applica-tion was increased over at least 2 weeks. The intradermal injec-tion of Potassium Ricinoleate induced a significant antinocicep-tive effect that lasted for at least 3 weeks (Vieira et al. 2000).

Effect on Enzyme ActivityRicinoleic Acid

In a study by Gaginella et al. (1978), isolated villus cellsfrom the small intestine of the hamster were used to deter-mine whether Ricinoleic Acid stimulates intestinal adenylatecyclase. In the adenylate cyclase assay, activity of the enzymewas determined using a method that is based upon the conver-sion of [α−32P]ATP to [32P]cyclic AMP. The cell homogenates(30 to 50 µg of protein per tube) were incubated for 20 min.Ricinoleic Acid concentrations of 10−9 to 5 × 10−3 M did notcause dose-dependent stimulation of adenylate cyclase. Signifi-cant (p < .05), but slight, stimulation of adenylate cyclase wasnoted at a concentration of 10−5 M, and higher concentrationsinhibited basal activity. Prostaglandin E1, which is chemicallysimilar to Ricinoleic Acid, was a potent stimulant of adenylatecyclase activity, causing dose-related stimulation (p < .001) ofadenylate cyclase at concentrations of 10−9 to 10−4 M.

Simon and Kather (1980) studied the modulation of adenylatecyclase and cAMP-phosphodiesterase, key enzymes of cAMPmetabolism, by Ricinoleic Acid in human colonic mucosa.The experiments were performed using histologically normalcolonic mucosa obtained from eight patients (five males, threefemales) who were undergoing hemicolectomy for carcinomaor diverticulosis. Adenylate cyclase activity was determinedaccording to the method of Salomon et al. (1974), and cyclicAMP phosphodiesterase activity was determined according tothe method of Poch (1971). Ricinoleic Acid was tested at con-centrations ranging from 1 × 10−8 to 5 × 10−4 mol/l. Basaladenylate cyclase activity in homogenates of human colonic mu-cosa averaged 250 pmol cAMP/mg protein/15 min. Mean basalcAMP phosphodiesterase activity was 150 ± 15 pmoles per mgprotein per minute.

Over the range of concentrations tested, dose-related stimu-lation of the large bowel adenylate cyclase was not observed.Basal activity of adenylate cyclase was inhibited at concentra-tions above 1 × 10−5 mol/l. Ricinoleic Acid did not influencesoluble cAMP phosphodiesterase activity over the range of con-centrations tested. Ricinoleic Acid was an ineffective stimulus ofhuman colonic adenylate cyclase, and also was not a competitive



inhibitor of soluble cAMP phosphodiesterase activity (Simonand Kather 1980).

In a study by Vanderhoek et al. (1980), the effect of Rici-noleic Acid on the oxygenation of [1-14C]arachidonic acid byplatelet cyclooxygenase and lipoxygenase enzymes was moni-tored using an oxygen electrode and by analysis of the radioac-tive products formed. The enzymes were obtained from humanplatelet concentrates (3 to 4 days old). Ricinoleic Acid did notappear to have an effect on either enzyme. The concentration ofRicinoleic Acid that was required for half-maximal inhibitionof lipoxygenase or cyclooxygenase activity was >300 µM.

Beubler and Schrirgi-Degen (1992) studied the stimula-tion of enterocyte protein kinase C by laxatives in vitro us-ing intestinal epithelial cell (from female Sprague-Dawley rats)preparations. A protein kinase C assay system was used todetermine the activity of protein kinase C. This assay sys-tem is based on protein kinase C–catalyzed transfer of the γ -phosphate group of adenosine-5′-triphosphate to a peptide thatis specific for protein kinase C. Ricinoleic Acid (dissolved inDMSO) stimulated protein kinase C activity in a concentration-dependent manner within the concentration range of 2 to200 µg/ml.

Effect on Uridine UptakeAt a concentration of 50 µM, Ricinoleic Acid suppressed

the uptake of uridine into human diploid fibroblasts in culture(Polgar and Taylor 1977).

Effect on Lipid MetabolismCastor Oil

Ihara-Watanabe et al. (1999) evaluated the effect of the fol-lowing diets on lipid metabolism using groups of five male Wis-tar rats (3 weeks old): 10% castor oil, 10% high-oleic saffloweroil, and 10% coconut oil. The diets were prepared in the absenceor presence of dietary cholesterol, and were fed ad libitum for20 days. On day 20, blood samples were obtained and liver andperirenal adipose tissues were excised. Serum and hepatic lipidswere analyzed for total cholesterol, high-density lipoprotein, tri-acylglycerols, and phospholipids.

Body weight gain and food intake were lowest for rats fedthe castor oil diet enriched with cholesterol, but not for rats fedcholesterol-free diets. Body weight gain to consumption ratioswere similar among all of the groups. Compared to rats fed thehigh-oleic safflower oil diet (enriched with cholesterol), rats fedthe castor oil diet enriched with cholesterol had decreased liverweights (g/100 g of body weight). Data on liver weights werenot presented in the study.

Values for total cholesterol and phospholipids in the serumwere significantly decreased in rats fed castor oil, compared torats fed high-oleic safflower oil in the absence or presence ofcholesterol. For cholesterol-enriched diets, the lowest value forserum high-density lipoproteins was reported for the castor oildietary group. No significant differences in serum triacylglycerol

occurred between either of the dietary groups (with or withoutcholesterol in the diet).

Compared to the high-oleic safflower oil dietary group (withor without cholesterol), significantly decreased (p < .05) hep-atic triacylglycerol concentrations were reported for the cas-tor oil dietary group. For cholesterol-enriched diets, the castoroil and coconut oil dietary groups had significantly increased(p < .05) hepatic cholesterol when compared to the high-oleicsafflower oil dietary group. It was concluded that castor oil had ahypocholesterolemic effect in rats in this study (Ihara-Watanabeet al. 1999).

Effect on Leukocyte Infiltration andProstaglandin SynthesisCastor Oil

Ohia et al. (1992) used castor oil as a vehicle control in astudy evaluating the effects of steroids and immunosuppres-sive drugs on endotoxin-induced uveitis in rabbits. The vehi-cle control group consisted of four male New Zealand rabbits(weights = 1.5 to 2.0 kg). The animals were injected intramus-cularly with castor oil (dose = 2 mg/kg). At 1 h post injec-tion, both eyes of each rabbit were cleansed and anesthetized.This procedure was followed by the intravitreal injection of Es-cherichia coli endotoxin (100 ng). The animals were killed 24 hafter injection of the endotoxin. Aqueous humor was obtainedand leukocytes were counted. The eyes were then enucleatedfor microscopic examination. Compared to saline-treated con-trols, castor oil significantly reduced the infiltration of leuko-cytes and the prostaglandin E2 (inflammatory mediator) contentof the aqueous humor and iris-ciliary body. The authors con-cluded that Castor Oil had an anti-inflammatory effect in thisstudy.

Effect on Cytokine-Induced Endothelial Cell ActivationSodium Ricinoleate

De Caterina and Bernini (1998) evaluated the relationshipbetween structural differences in fatty acids and the inhibitionof endothelial activation, taking into consideration that dietarylong-chain fatty acids may influence processes that involve en-dothelial activation (e.g., inflammation and atherosclerosis). Totest for a potential stimulatory effect of fatty acids on adhesionmolecule expression, sodium salts of saturated, monounsatu-rated (Sodium Ricinoleate included), and n-6 and n-3 polyun-saturated fatty acids were each incubated alone (test concentra-tion = 25 µM) with human saphenous vein endothelial cells(HSVECs) for 72 h. The 72-h incubation period was followedby 16 h of stimulation with the cytokine interleukin (IL)-1α inthe continuous presence of fatty acid salt. At the end of the in-cubation period, vascular cell adhesion molecule-1 (VCAM-1)expression was assessed using a cell surface enzyme immunoas-say (EIA).

Sodium Ricinoleate significantly inhibited (considered mod-est; p < .05) cytokine-induced endothelial adhesion molecule


CASTOR OIL 51

expression. DHA inhibited VCAM-1 expression (p < .01) mostpotently (De Caterina and Bernini 1998).

De Caterina and Bernini (1998) also conducted an experimentto determine whether the fatty acid sodium salts may induce en-dothelial activation in the absence of cytokines. The salts wereincubated with endothelial cell monolayers for 24 h. Incubationperiods prior to detection of adhesion molecule surface expres-sion varied from 0 to 72 h. Neither Sodium Ricinoleate (25 µM)nor any other fatty acid sodium salt induced adhesion moleculeexpression, as assessed by EIA.

Ricinoleic AcidIn a study by De Caterina et al. (1995), the effect of Rici-

noleic Acid on VCAM-1 expression was evaluated using rabbitcoronary artery endothelium in vitro. VCAM-1 (marker for en-dothelial cell activation) is a surface protein that is not expressedby endothelial cells in vitro, but is inducible by exposure to in-flammatory stimuli such as bacterial endotoxin, IL-1, or tumornecrosis factor α (TNFα). Ricinoleic Acid significantly reducedIL-4–induced VACM-1 expression (50% inhibitory concentra-tion between 10 and 100 µM). Neither cell number nor viabilitywas increased in this concentration range. Ricinoleic Acid didnot inhibit TNFα-induced VACM-1 expression to any signifi-cant extent.

Effect on Prostaglandin SynthesisCastor Oil

Gao et al. (1999) evaluated the effect of castor oil in the dieton the synthesis of prostaglandin E2 (PGE2) and the induction oflabor using two groups of eight pregnant Wistar rats (at gestationday 18; test and control groups, respectively). Two milliliters ofcastor oil–containing diet were administered by gavage daily fora total of four feedings. The diet (labor-inducing diet) consistedof castor oil (30 ml) + one chicken egg, blended and heated toa thick consistency. At 4 h after the fourth feeding, the pregnantfemales were killed. Compared to the control group, a significantincrease in concentrations of PGE2 in tissues of the intestinalmucosa, placenta, amnion, and amniotic cells was noted in testanimals. The authors stated that the increased synthesis of PGE2

“is a key of” the initiation of labor that is induced by a castor oildiet.

CytotoxicitySodium Ricinoleate

Gaginella et al. (1977b) evaluated the cytotoxicity of Rici-noleic Acid using epithelial cells that were isolated from thesmall intestines of male Syrian hamsters. Cytotoxicity was as-sessed by exclusion of trypan blue, the release of intracellular(prelabeled) 51Cr, and inhibition of the cellular uptake of 3-O-methylglucose. The results produced by all three methodsindicated that Sodium Ricinoleate produced a dose-dependentcytotoxicity.

For the trypan blue exclusion method, Sodium Ricinoleatecaused dose-related increases in cytotoxicity at concentrationsof 0.1 to 5.0 mM. Death of all cells was noted at a concentrationof 2.0 mM. Results for control incubation in the 51Cr release as-say indicated that 26.8 ± 1.7% of 51Cr, initially within or boundto the cells, was released into the medium. Sodium Ricinoleateinduced concentration-dependent (0.1 to 5 mM Sodium Rici-noleate) increases in 51Cr release, from 4.2% to 54.8% above thecontrol value. In the 3-O-methylglucose uptake assay, SodiumRicinoleate inhibited the uptake of 3-O-methylglucose over aconcentration range of 0.1 to 2.0 mM (Gaginella et al. 1977b).

In a study by De Caterina and Bernini (1998), the cytotoxi-city of Sodium Ricinoleate and other fatty acid sodium salts inhuman saphenous vein endothelial cell cultures was evaluated.Cell count, trypan blue exclusion, and [3H]leucine incorporationinto total cell-associated and released proteins were monitored.For the latter of the three, trichloroacetic acid precipitation oftotal cell extracts and cell supernates was performed. At con-centrations ≤25 µM, Sodium Ricinoleate and other fatty acidsodium salts did not induce significant toxicity (based on cellcount and trypan blue exclusion) for periods up to 72 h prior tocytokine stimulation.

Antimicrobial ActivityCastor Oil

Morris et al. (1979) evaluated the antimicrobial activity ofcastor oil on Staphylococcus aureus, Escherichia coli, and Can-dida albicans using the Petri plate–paper disc procedure. Paperdiscs were soaked with 20 µl of a 10% Castor Oil solution, andthe discs were immediately applied to solidified, seeded agar(1 disc per plate). The plates were incubated for 10 to 24 h.Discs containing 95% ethanol (20 µl) served as negative con-trols. Castor Oil did not have antimicrobial activity on any ofthe strains tested.

Sodium RicinoleateWhiteside-Carlson et al. (1955) studied the effect of Sodium

Ricinoleate on cell division using a laboratory strain of E. coli.Sodium Ricinoleate was tested over a concentration range of1 to 5 mg/ml of medium. The cultivation of E. coli on nutri-ent agar that was saturated with Sodium Ricinoleate caused thedevelopment of filamentous forms during the first h of loga-rithmic growth. By the end of the log phase, organisms of nor-mal morphology were observed. When agar containing SodiumRicinoleate was adjusted to pH values of 5 to 8, filament for-mation was more marked and persisted for longer periods atthe more alkaline pH value. The utilization of liquid proteose-peptone medium (with periodic readjustment of the pH to arange of 7.6 to 7.8) resulted in maintenance of the cells in fila-mentous form throughout the entire growth cycle. The tendencytoward filament formation was reduced by lowering the incuba-tion temperature to below 37◦C. The results of this study indicate



that Sodium Ricinoleate interfered with cell division in E. coli,causing the organisms to develop as filaments.

Mordenti et al. (1982) studied the activity of Sodium Rici-noleate against Streptococcus mutans strain 6715-13 (plaque) invitro. The minimum inhibitory concentration of Sodium Rici-noleate against S. mutans was 1% (or 3.12 × 10−2 M). Duringtesting for the minimum inhibitory concentration, the followingfour distinct concentration-dependent cell growth and acid pro-duction phenomena were identified: (1) no cell growth, pH >

6.8; (2) cell growth, medium pH > 6.8; (3) cell growth, mediumpH of 5.2 to 6.8; and (4) cell growth, medium pH < 5.2. Itwas concluded that Sodium Ricinoleate had bactericidal activityin this assay. In subsequent experiments, wire-adherent plaquespecimens were treated with various concentrations of SodiumRicinoleate. The intact plaque samples survived in each of thesetests. The authors stated that the ability for Sodium Ricinoleateto kill bacteria in suspension, but not in intact plaque, clearlydemonstrates the absence of a correlation between antibacterialactivity against cells in suspension and antiplaque activity.

Other Biological EffectsCastor Oil

Capasso et al. (1986) evaluated the effect of castor oil onthe formation of histamine, 5-hydroxytryptamine (5-HT), andprostaglandin-like material (PG-LM) in the rat intestine usingmale, fasted Wistar-Nossan rats (number and weights not stated).Castor oil (dose = 2 ml/rat) was administered by gavage. Follow-ing the onset of diarrhea, the animals were killed, and sections ofcolon removed. Untreated rats served as controls. Castor oil in-duced an approximately fourfold increase in PG-LM (p < .01)and a threefold increase in histamine and 5-HT (p < .01). Adecrease in the Castor oil–induced colonic formation of PG-LM was noted following pretreatment of the animals with in-domethacin (inhibitor of prostaglandin biosynthesis) or hydro-cortisone. It was concluded that these data support the idea thatthe laxative effect of castor oil is the result of increased intestinalproduction of PG-LM, histamine, and 5-HT.

A study was conducted by Pinto et al. (1989) to determinewhether oral administration of castor oil leads to changes inthe levels of platelet-activating factor (PAF) formed by intesti-nal tissue, and whether these changes are related to intestinaldamage. Fasted, male Wistar-Nossan rats (number not stated;weights = 130 to 140 g) were used. Castor oil (dose = 2 ml/rat)was administered orally, and the animals were killed.

At 3 h post dosing, the formation of PAF by segments ofrat intestine was significantly increased (compared to controlrats treated with olive oil) in the following intestinal segments:duodenum (p < .001), jejunum (p < .01), ileum (p < .2), andcolon (p < .1). At macroscopic examination, extensive regionsof hyperemia were noted in the entire intestinal mucosa. Theduodenum and jejunum regions were the most severely affected.No increase in PAF was noted in control rats dosed with olive oil.

Compared to control rats dosed with olive oil, castor oil also

increased the intraluminal release of acid phosphatase (AP) inthe duodenum and jejunum (p < .01), and a similar trend wasreported for the ileum and colon (p < 0.2 to .1). A correlationbetween increased release of AP and intestinal hyperemia wasestablished. The authors noted that the results of this study sug-gest that PAF is involved in the mechanism underlying castoroil–induced intestinal damage (Pinto et al. 1989).

In a study by Blair et al. (2000), the affinity of castor oil andnumerous other chemicals for the estrogen receptor (from uteriof ovariectomized Sprague-Dawley rats) was evaluated using avalidated estrogen receptor competitive binding assay. In thisassay, the ability for a chemical to compete with [3H]estradiol([3H]E2) for the estrogen receptor was determined, based on IC50

(concentration resulting in 50% inhibition of [3H]estradiol bind-ing) values. All assays were replicated a minimum of two times.The mean IC50 for Castor oil was>1.0 × 10−4 M. Mean IC50 val-ues for 4-heptyloxyphenol and phenophthalein (both classifiedas moderate estrogen receptor binders) were 6.75 × 10−5 ±0.75 × 10−5 and 6.73 × 10−6 ± 1.79 × 10−6, respectively.The binding affinity of castor oil for the estrogen receptor wasnot classified.

Ricinoleic AcidIn a study by Grainger et al. (1982), the effect of Ricinoleic

Acid on lymph flow in outerperfused segments of cat ileum wasevaluated. The cats were anesthetized and a segment of ileumwith intact innervation and lymphatic drainage was isolated andperfused by the intact mesenteric artery. A cannula was insertedinto a large lymphatic vessel emerging from the mesenteric pedi-cle, and lymph flow was determined by observing lymph move-ment in a calibrated pipette that was connected to the lymphaticcannula. The mean control (± SE) value for intestinal lymphflow in the experiments was 0.048 ± 0.005 ml/min × 100 g.Net fluid secretion was stimulated by intraluminal instillation of5 mM Ricinoleic Acid. The peak increase in intestinal lymphflow produced by Ricinoleic Acid in all experiments was 6.3± 1.2 (n = 5) times the control. The maximal fluid excretionrate observed with Ricinoleic Acid was 0.43 ± 0.23 ml/min ×100 g.

Yagaloff et al. (1995) evaluated the inhibitory activity of a se-ries of fatty acids and fatty acid derivatives on [3H]leukotrieneB4 binding (LTB4) to pig neutrophil membranes using the LTB4

receptor binding assay. The most potent chemicals were 15-hydroxy-DGLA (20:3; Ki = 1 µM), eicosadienoic acid (20:2;Ki = 3 µM), and Ricinelaidic Acid (18:1; Ki = 2 µM). Rici-noleic Acid (18:1) had a Ki of 9 µM.

ANIMAL TOXICOLOGY

Acute Oral ToxicityCastor Oil

In a study by Capasso et al. (1994), castor oil (2 ml) wasadministered orally to ten male Wistar rats (weights = 160 to


CASTOR OIL 53

180 g). The animals were killed and two segments from stan-dardized regions of the duodenum and jejunum were visiblyevaluated for macroscopic damage. Mucosal injury was gradedaccording to the following scale: 0 (normal), 1 (hyperemia), 2(hyperemia with evidence of hemorrhage into the lumen), and 3(severe hemorrhage into the lumen).

Copious diarrhea was reported for all animals on days 3, 5,and 7 post dosing. Macroscopic damage, characterized mainlyby vasocongestion, was observed throughout the duodenum andjejunum. The injury observed ranged from mild (at 1 h) to severe(at 5 h), and was less severe at 7 h. Injury was not observed at0.5 or 9 h after dosing. Castor oil–induced mucosal damage wasassociated with statistically significant intraluminal release ofacid phosphatase.

In additional experiments (groups of 10 rats), mucosal dam-age induced by castor oil was exacerbated in the presence of a ni-tric oxide synthase inhibitor (Nω-nitro-l-arginine methyl ester),suggesting that nitric oxide provides protection against castoroil-induced mucosal damage (Capasso et al. 1994).

In a study involving male Crl:CD BR rats, the findings sug-gested that castor oil–induced diarrhea is the result of activationof NK1 and NK2 receptors by endogenous tachykinins (Crociet al. 1997).

In a study by Johnson et al. (1993), castor oil was ad-ministered orally to 12 ponies (17 months to 20 years old;weights = 160 to 250 kg). The ponies were randomly as-signed to two treatment groups and one control group (fourponies per group). Each animal received a single 2.5 ml/kgbody weight dose of castor oil via nasogastric tube. Diarrheaoccurred within 24 h of dosing. The animals were killed andnecropsied at 24, 48, and 72 h post dosing. Intestinal tis-sues were removed and subjected to gross and microscopicexamination.

In ponies killed at 24 or 48 h, gross lesions were most severein the cecum and ventral colon. At 24 h, the mucosa of the dis-tal jejunum, ileum, cecum, and ventral colon was diffusely red.Most of the ponies dosed with castor oil had generalized hyper-emia of the intestinal mucosa at 24, 48, and 72 h post dosing,and mesenteric, cecal, and colonic lymph nodes were edema-tous. Mucosal and submucosal edema of the ileum, cecum, andventral colon was noted in all ponies dosed with castor oil. At72 h post dosing, focal acute ulceration and intense mucosal hy-peremia of the glandular stomach was observed in three of fourponies dosed with castor oil.

Microscopic changes in the superficial enterocytes of the ce-cum and ventral colon that were characterized as follows: lossof microvilli; distortion of the cytoplasmic terminal web; ex-pansion of the cytoplasmic matrix, with formation of precipi-tates; and widening of intracellular spaces between junctionalcomplexes. Castor oil induced acute superficial enterocolitisin ponies. Dosing was associated with transient diarrhea, neu-trophilic inflammation, and mucosal erosion in the cecum andventral colon (Johnson et al. 1993).

Hydrogenated Castor OilThe acute oral toxicity of a 25% solution of Hydrogenated

castor oil in olive oil was evaluated in a study involving ten maleWistar rats (average body weight = 155 g). The test solution(dose = 10 g/kg) was administered via a gastric probe. Toxicsigns were not observed in any of the animals, indicating thatthe test substance was well tolerated. The LD50 was >10 g/kg(Allegri et al. 1981).

Ricinoleic AcidIn a study by Okui et al. (1964), male albino rats (number

not stated; weight = 120 ± 10 g) were injected intraperitoneally(i.p.) with 100 mg Ricinoleic Acid. All of the animals weredead within 24 h. The i.p. injection of a 5% Ricinoleic Acidemulsion (1 ml) was tolerable, but caused an increase in the fol-lowing: amount of ascites, conglutination of peritoneal organs,and swelling of the liver. However, histological changes werenot observed in liver specimens.

Cetyl RicinoleateIn an acute oral toxicity test performed by Laboratoire de

Recherche et d’Experimentation (1994), Cetyl Ricinoleate wasevaluated using five female NMRI EOPS mice (weights = 19 to22 g). Oral dosing (single dose 2000 mg/kg) was followed by a6-day observation period. None of the animals died, and clinicaland behavioral evaluations were normal. Weight gain was con-sidered satisfactory. The authors stated that Cetyl Ricinoleatewas non-toxic in this study.

Ethyl RicinoleateThe acute oral toxicity of Ethyl Ricinoleate was evaluated us-

ing 10 rats (weights and strain not stated). The acute oral LD50

exceeded 5.0 g/kg; one animal receiving this dose died. Thefollowing clinical signs were observed during the study: iso-lated instances of diarrhea, chromorhinorrhea, ptosis, and chro-modacryorrhea. At necropsy, gross observations were normal foreight animals. Necropsy of the remaining two animals revealedthe following changes in either one or both animals: red and/oryellow areas in the intestines, red areas in the stomach, mottledliver, mottled spleen, mottled kidneys, dark lungs, red exudatein the anogenital area, and a large amount of blood in the bladder(Research Institute for Fragrance Materials [RIFM] 2000).

Acute Dermal ToxicityEthyl Ricinoleate

The acute dermal toxicity of Ethyl Ricinoleate was evaluatedusing six rabbits (weights and strain not stated). The acute dermalLD50 exceeded 5.0 g/kg; one animal receiving this dose died.The following clinical signs were observed during the study:isolated instances of lethargy, diarrhea, ptosis, and yellow nasaldischarge, and moderate erythema (six rabbits), slight edema(one rabbit), and moderate edema (five rabbits). At necropsy,



gross observations were normal for three animals. Necropsy ofthe remaining animals revealed the following changes: red areasin the intestines, mottled liver, white nodules in the liver, darkareas in the lungs, mottled kidneys, pale kidneys, dark spleen,and dark areas in the stomach (RIFM 2000).

Acute Intravenous ToxicityCastor Oil

In a study by Lorenz et al. (1982), castor oil was administeredintravenously (single bolus dose = 0.1 ml/kg) to each of eightanesthetized adult mongrel dogs (four males, four females; meanweight = 20.5 kg). Blood for histamine assays was obtainedat 2, 5, 10, 15, and 20 min post dosing. The incidence of thefollowing signs was determined: erythema, hives (papules andwheals), edema, defecation, tachypnea, hypotension, and death(circulatory arrest). None of the animals died, and erythema(one animal; score not stated) was the only clinical sign that wasreported. An increase in blood histamine occurred in one of theeight animals. At 2 min post dosing, the increase was 0.6 ng/mlof whole blood (maximum response) in this animal. The authorsconcluded that castor oil was ineffective in terms of its abilityto cause histamine release.

Short-Term Oral ToxicityCastor Oil

Masri et al. (1962) conducted an experiment in which tenmale weanling rats (4 weeks old; mean weight = 42.2 ± 0.6 g)were fed (ad libitum) 10% castor oil for approximately 5 weeks.A similar control group (mean weight = 42.2 ± 0.5 g) re-ceived corn oil in the diet. The animals were observed forgrowth and catharsis throughout the duration of the study. Cas-tor oil in the diet did not induce catharsis in any of the 10rats, and growth of these animals was comparable to that ob-served in the control group. At the end of the experiment,mean weights for test and control rats were 155.6 ± 4.6 and160.5 ± 4.1 g, respectively. Grossly, there were no abnormal-ities. Additionally, no abnormalities of the perirenal fat werenoted.

Short-Term Subcutaneous ToxicityCastor Oil

In a study by Migally (1979), the morphology of the adrenalcortex was examined after injection of a commonly used vehicleconsisting of castor oil and benzyl benzoate. Twenty-five adultC57 BL/6J mice (weights not stated) were divided into the fol-lowing groups: group I (five intact control mice); group II (fivesham-injected mice); group III (five mice each injected with 0.1ml castor oil); group IV (five mice each injected with 0.1 mlbenzyl benzoate; and group V (five mice each injected with 0.1ml castor oil and benzyl benzoate [4:1]). The mice were injectedsubcutaneously daily for four weeks and then killed. Necropsywas then performed and tissues prepared for light and electronmicroscopic examination.

Using electron microscopy, parenchymal cells containingelectron-dense lipid inclusions were observed in the zona fas-ciculata of adrenal glands from mice injected with castor oil.By light microscopy, there was no difference between adrenalglands from control mice and mice injected with the vehicle con-sisting of castor oil and benzyl benzoate; however, by electronmicroscopy, the following variations were observed: profounddisruption of parenchymal mitochondria in the zona fasciculataand a noticeable increase in size for some of the mitochondria.The vesicular orientation of the inner mitochondrial membranewas lost (i.e., random orientation), and diminution of the mito-chondrial matrix was also observed.

Unlike the controls, the macrophages of exposed animalshad large vacuoles filled with globular material. In the zonareticularis and inner zona fasciculata, parenchymal mitochon-dria with circular orientation of the inner membrane (normallyfew) were noticeably increased in number. The authors notedthe appearance of similar mitochondria following adrenocorti-cotrophic hormone (ACTH) stimulation, and that the alterationof ACTH release has been shown to result from stress. Theauthor concluded that subcutaneous injection of the castor oil–benzyl benzoate vehicle caused morphological alterations thatare suggestive of stress-induced changes (Migally 1979).

Subchronic Oral ToxicityCastor Oil

In a study by the National Toxicology Program (NTP) (1992),the subchronic oral toxicity of castor oil was evaluated usinggroups of 10 male and 10 female F344/N rats (mean bodyweights = 126 to 132 g [males]; 107 to 110 g [females]) andgroups of 10 male and 10 female B6C3F1 mice (mean bodyweights = 22.6 to 23.0 [males]; 17.2 to 17.7 [females]). In thecore study, five groups of test animals (mice or rats) receiveddiets containing 0.62%, 1.25%, 2.5%, 5.0%, or 10% castor oilcontinuously for 13 weeks. Two control groups of 20 rats and20 mice received diets that did not contain castor oil.

Ten additional rats/sex were included at each dose level forevaluation of hematological and clinical chemistry parameters.On days 5 and 21, these animals were anesthetized with CO2 andblood samples were obtained. These animals were killed follow-ing blood collection on day 21. Blood samples for hematologyand clinical chemistry were also collected from core-study ratsat the end of the study. Also, at the end of the 13-week study, allcore-study animals were killed and complete necropsies wereperformed, including complete microscopic examination on tis-sues, on all test and control animals.

No effect on survival or significant differences in averagefood consumption were noted in any of the five groups ofmale and female rats fed castor oil. There were no signifi-cant differences in mean body weights between test and controlgroups.

The following hematological effects were reported formale rats: a slight decrease in mean corpuscular hemoglobin


CASTOR OIL 55

concentration (MCHC) (10% castor oil diet), a statisticallysignificant decrease (p < .05) in mean corpuscular volume(MCV) (10% castor oil diet), a decrease in mean corpuscularhemoglobin (MCH) (5% and 10% castor oil diets), and an in-crease in platelets (1.25%, 5%, and 10% castor oil diets). Theonly hematological abnormality reported for female rats was astatistically significant (p < .05) decrease in reticulocyte counts(0.62% or 10% castor oil diets). The authors did not considerthe hematological effects to be biologically significant. A dose-related increase (treatment-related) in the activity of serum al-kaline phosphatase was noted in male and female rats at days 5and 21, and at the end of the study.

Increased heart-to-body weight ratios were reported for malerats that received 0.62%, 2.5%, and 10.0% castor oil diets;however, no increase in absolute heart weight was noted. Theobserved differences in organ-to-body weight ratios were notconsidered treatment related. Microscopically, no morphologicchanges were associated with the slight differences in organweights between the dietary groups.

Compared to controls, liver weights were increased in maleand female mice receiving diets containing 5% or 10% castoroil. Increased kidney weights were reported for female mice thatreceived 5% or 10% castor oil in the diet. Microscopically, therewas no evidence of morphologic changes that could be been as-sociated with the slight differences in organ weights between thegroups tested. Additionally, there was no evidence of treatment-related lesions in any of the tissues or organs that were examined(all dietary groups).

The authors concluded that diets containing up to 10% castoroil to B6C3F1 mice and F344/N rats was not associated withtoxicity to any specific organ, organ system, or tissue in thisstudy (NTP 1992).

Hydrogenated Castor OilIn a preliminary feeding trial (preparatory to the 16-week

feeding study reported below) by Binder et al. (1970), the sub-chronic oral toxicity of 5%, 10%, and 20% Hydrogenated Cas-tor Oil [HCO] (effective concentrations of 4.33%, 8.65%, and17.3%, respectively) in the diet was evaluated using groups ofthree weanling female rats (Slonaker substrain of Wistar strain).The sample of HCO that was incorporated into the diet contained86.5% 12-hydroxystearic acid, 10.3% nonoxygenated acids, and3.2% 12-ketostearic acid. The three groups were fed for 90 days,and the control group received diet only. At necropsy, organweights were recorded and numerous tissues were prepared formicroscopic examination. Prior to necropsy, blood samples wereobtained for hematological evaluation.

A reduced growth rate in rats fed 8.65% and 17.3% Hydro-genated Castor Oil, respectively, was the only abnormality thatwas noted. The authors stated that it is likely that HydrogenatedCastor Oil was poorly digested because of its high melting point.Therefore, the poor body weight gains may have been due to thelower caloric density of the diets containing Hydrogenated Cas-tor Oil at concentrations ≥8.65%.

To confirm the authors’ explanation of the results, the exper-imental trial was repeated with Hydrogenated Castor Oil at con-centrations of 1%, 5%, and 10% in corn oil (effective concentra-tions of 0.865%, 4.33%, and 8.65%, respectively). The amountof corn oil added to the individual diets was 9%, 15%, and 10%.Corn oil (20%) was present in the control diet. Necropsy wasperformed at the end of the 90-day feeding period. The growthrate for rats fed 8.65% Hydrogenated Castor Oil in the diet wasequivalent to that of the other dietary groups. Based on organweight determinations and the results of hematological and mi-croscopic evaluations, no adverse effects were observed (Binderet al. 1970).

In the 16-week feeding study (Binder et al. 1970), groups of15 male albino rats (Slonaker substrain of Wistar strain, weights= 43 to 83 g) received diets containing the following oils: group1 (fed 0.865% HCO + 19% corn oil for 16 weeks), group 2(0.865% HCO + 19% corn oil for 8 weeks, then 20% cornoil for 8 weeks), group 3 (8.65% HCO + 10% corn oil for 16weeks), and group 4 (8.65% HCO + 10% corn oil for 8 weeks,then 20% corn oil for 8 weeks).

The effective dietary concentrations of Hydrogenated CastorOil in the 0.865% and 8.65% diets were 0.865% and 8.65%,respectively. The control group received 20% corn oil in the dietfor 16 weeks.

At 4, 8, 12, and 16 weeks, the number of animals on the HCOdiets that were alive was 33, 30, 12, and 6 rats, respectively. Thecorresponding number of rats remaining on the control diet was15, 15, 12, and 6.

Weight differences due to the different diets at 4 and 8 weekswere not statistically significant at the 95% level. However, at12 weeks, rats on the 8.65% HCO diet weighed significantlyless than rats on the control diet or 0.865% HCO diet. At16 weeks, the weight gain of rats on the control diet was signif-icantly greater than that of rats on the 8.65% HCO diet for 16weeks or on the 8.65% HCO diet for 8 weeks + control diet forthe remaining 8 weeks. The weight gain of rats on the 0.865%HCO diet was not significantly different from that of rats on thecontrol diet. Except for the reduced growth rate in rats receivingthe 8.65% HCO diet, no adverse effects were observed (Binderet al. 1970).

Ocular Irritation/ToxicityCastor Oil

Carpenter and Smyth (1946) evaluated the ocular irritationpotential of castor oil using albino rabbits. The eyelids wereretracted, and undiluted castor oil (0.5 ml) was applied to thecenter of the cornea. At approximately 1 min post instillation, theeyelids were released. Reactions were scored 18 to 24 h later. Todetermine the score for ocular injury, the individual numericalscores for each eye were added together and then divided bythe number of eyes (usually 5). An ocular injury score of 5.0represents severe injury, and corresponds to necrosis (coveringapproximately three-fourths of the corneal surface) that is visibleonly after staining or a more severe necrosis covering a smaller



area. An injury grade of 1 (maximum score possible = 20) wasreported for castor oil.

In a study by Guillot et al. (1979), the effects of various oils(used in cosmetics) on the rabbit eye were assessed according tothe official French methods. Following the instillation of undi-luted castor oil (no ocular rinsing), no corneal involvement wasfound. However, slight congestion of the iris and conjunctivawas observed.

Castor oil served as one of the vehicle controls in a study byBehrens-Baumann et al. (1986) investigating the effect of topicalcyclosporin A on the abraded and intact rabbit cornea. Two castoroil vehicle control groups of outbred male rabbits were used. Inboth groups (10 eyes/group), 10 drops of castor oil were instilleddaily for 3 weeks, and all eyes were examined using a slit-lamp.At the end of the 3-week period, the animals were killed and theircorneas were excised and prepared for scanning and transmis-sion electron microscopy. For eyes (no corneal abrasion) treatedwith Castor oil and examined by scanning electron microscopy,there were increased numbers of medium dark and dark epithe-lial cells (compared to the normal epithelium). The cell borderswere intact and the number of holes was reduced. By transmis-sion electron microscopy, corneal endothelial cells were intact.By scanning electron microscopy, an intact cell pattern, withmore cell microstructures than normal, for the corneal endothe-lium was reported. Ultrathin sections appeared normal. The au-thors concluded that castor oil did not damage the rabbit cornealepithelium or endothelium (Behrens-Baumann et al. 1986).

Skin IrritationCastor Oil

Butcher (1951) evaluated the effect of castor oil and othersubstances on rat epidermis using, primarily, 22-day-old albinoor Long-Evans rats or rats of either strain in which the hairfollicles were in the resting stage; older animals were also used.A total of 216 rats were used in the experiments. Using drycotton, castor oil was gently swabbed onto a large area of thedorsum (clipped free of hair) daily for 5 days to 2 weeks. At theend of the application period, small areas of skin were obtainedfrom the backs of treated and control (one rat/litter) rats andexamined microscopically. Castor oil was described as having amild effect on the epidermis. The alteration was mainly confinedto the stratum granulosum, where the cells were more numerousand the granules were more evident, compared to the litter-matecontrols.

In a study by Meyer et al. (1976), castor oil (undiluted, 4drops) was rubbed onto either side of the shaved left flank ofeach of six albino guinea pigs (weights = 300 to 400 g) andsix young pigs (weights = 10 to 12 kg) within 30 s on 10 suc-cessive days. The opposite side served as the control field, andwas massaged only. The animals were killed on day 11. A tissuesection (1 × 1 cm) was excised from the center of the test fieldsand prepared for microscopic examination. Five to eight sec-tions of 7 µm thickness per test area were used for evaluation.

A micrometer eyepiece was inserted into the microscope, andepidermal width measurements (25 per individual field; 400×magnification) were made. Castor oil induced slight reddeningat the application site.

Microscopically (pigs and guinea pigs), hyperplasia, with anincrease in the cell and nuclear density of the basal cell layers,was observed. Additionally, widening of the granular layer andthick keratohyalin granules were observed. Average epidermalwidths (25 measurements) were as follows at the end of the10-day application period: guinea pigs (control, 27.9 µm; test,94.3 µm) and pigs (control, 26.5 µm; test, 32.3 m) (Meyer et al.1976).

Rantuccio et al. (1981) evaluated the effect of undiluted cas-tor oil on the skin of five female albino rabbits (6 months old;mean weight = 2500 g). The test substance (0.5 ml) was gentlymassaged into depilated skin of the right flank of each rabbitdaily for 30 days. Following each daily application, the test sitewas covered with a simple protective dressing. Two small skinpunch biopsies were obtained from the right and left (control)flank on days 10, 20, and 30. Macroscopic skin changes includedslight erythema and slight edema. Microscopic examination ofpunch biopsies obtained at day 10 revealed “clear-cut” acan-thosis with vacuolization and disorganization of the basal layer.These changes were associated with some infiltration of the der-mis by mononuclear cells and fibrocytes. After days 20 and30, the epithelial changes became progressively more evident.However, the appearance of the infiltrate remained unchanged.

In a study by Guillot et al. (1979), the effect of various oilsthat are used in cosmetics on rabbit skin was assessed accordingto the official French methods. An open skin irritation test andrepeated application test (8 weeks) were performed. The authorsstated that the two samples of undiluted castor oil, as well as 10%aqueous castor oil, were well tolerated.

In a study by Motoyoshi et al. (1979), the skin irritation po-tential of castor oil (undiluted) was evaluated using six albinoangora rabbits (average weight = 2.6 kg). The test substance(0.1 g of liquid or semisolid) was applied for 24 h to two testareas (clipped free of hair) on the dorsal surface of each an-imal. A plastic collar was wrapped around the neck of eachanimal and remained throughout the application period, afterwhich reactions were scored according to the following scale:− (no reddening) to +++ (severe reddening, beet redness). At30 min, after reactions were scored, the test areas were clippedfree of hair and castor oil was reapplied according to the sameprocedure. A third application of Castor Oil occurred 48 h later,and reactions were scored. Reactions were scored again at 72 h.Castor oil was severely irritating to the skin of rabbits (score=3).

The skin irritation potential of Castor oil was also evaluatedusing guinea pigs, rats, and miniature swine in this study.

Undiluted castor oil (0.1 g) was applied daily to dorsal skin(clipped free of hair) in the mid-lumbar region of six male Hart-ley guinea pigs (weights = 350 to 500 g) and six male Wistar rats(weights = 250 to 350 g). The period of testing, the frequency ofapplication, and the method of evaluation of skin reactions were


CASTOR OIL 57

the same as those in the preceding test involving albino angorarabbits. Castor oil was mildly irritating to the skin of guinea pigsand rats.

The skin irritation potential of undiluted castor oil was eval-uated using six miniature swine of the Pitman-Moore strain(1 month old). The test substance (0.05 g) was introduced under a15-mm-diameter patch that was secured with adhesive tape. Theentire trunk was wrapped with rubberized cloth during the 48-hexposure period. Reactions were scored after patch removal. Thegrading scale was the same as that used in the experiment in-volving albino angora rabbits that is summarized above. Castoroil was not irritating to the skin of miniature swine (Motoyoshiet al. 1979).

Ricinoleic AcidIn a study by Vieira et al. (2000), 8 to 10 male Swiss mice re-

ceived a single topical application of Ricinoleic Acid (in peanutoil, 10 mg/mouse) on the ventral surface of the paw. Neithererythema nor edema of the paw was observed.

Vieira et al. (2001) presented results on the skin irritationpotential of Ricinoleic Acid, using groups of six male albinoDunkin-Hartley guinea pigs, in a study evaluating pro- andanti-inflammatory effects of Ricinoleic Acid (concentration notstated). Ricinoleic Acid (0.1 ml, in peanut oil) was administeredtopically to the entire eyelid surface. The thickness of the eyelidwas measured in mm using ophthalmic microcallipers. Topi-cal treatment with Ricinoleic Acid (10, 30, or 100 mg/guineapig) caused eyelid reddening and edema. A moderate, dose-dependent eyelid edema was reported as follows: 0.12 ± 0.05mm (10 mg Ricinoleic Acid), 0.18 ± 0.02 mg (30 mg), and 0.23± 0.1 mm (100 mg). Maximal edema was achieved at 2 h post-application. The application of Ricinoleic acid vehicle did notcause any appreciable edema.

Cetyl RicinoleateIn a skin irritation study conducted by the Laboratoire de

Recherche et d’Experimentation (1994), Cetyl Ricinoleate (testconcentration not stated) was evaluated using three male NewZealand albino rabbits. Erythema and edema were observed inthree and two rabbits, respectively, up to 72 h post application.At 72 h, one rabbit had an erythema score of 2 and the remainingtwo had an erythema score of 1. Edema (score = 1) was observedin two rabbits at 72 h. All reactions were totally reversible at 7days post application. Cetyl Ricinoleate was a nonirritant in thisstudy.

Zinc RicinoleateIn a study by International Bio-Research, Inc. (1977a),

the skin irritation potential of 10% Griillocin HY 77 (nowTEGODEO HY 77) in soybean oil was evaluated using sixNew Zealand albino rabbits (weight range = 2.4 to 2.6 kg).TEGODEO HY 77 (trade name mixture for Zinc Ricinoleate)has the following composition: Zinc Ricinoleate (more than50%), triethanolamine (10% to 25%), dipropylene glycol (1%

to 5%), and lactic acid (1% to 5%). The diluted test substance(concentration after dilution not stated) was applied to clippedskin on two areas of the back of each animal; one of the areaswas abraded. The test sites were covered with occlusive patches(secured with adhesive tape) and the entire trunk was wrappedin a rubber sleeve. The patches remained in place for 24 h andreactions were scored at 24 and 72 h post application as fol-lows according the Draize scale: 0 (no erythema) to 4 (severeerythema [beet redness] to slight eschar formation [injuries indepth] and 0 (no edema) to 4 (severe edema, raised more than 1mm and extending beyond area of exposure).

At 24 h post application, well-defined erythema was observedat the abraded test sites of all six rabbits and slight erythema wasobserved at the intact sites of four rabbits. Well-defined erythemawas observed at the intact sites of two rabbits during the 24-hreading. At 72 h post application, five rabbits had mild erythemaat the abraded site and two rabbits had the same reaction at theintact site. Using the data for abraded and intact test sites, a totalprimary irritation index of 1.1 was calculated (International Bio-Research, Inc. 1977a).

Effect on Intestinal MembranesRicinoleic Acid

In a study by Morehouse et al. (1986), a single 0.1 ml dose ofRicinoleic Acid (100 mg/ml) was administered intragastricallyto fasted, specific pathogen-free mice (strain CD-1, number notstated). This dosage of Ricinoleic Acid was determined, on aweight basis, to be approximately the dosage that is used ther-apeutically in humans. Groups of mice were killed at variousintervals, and light microscopy and transmission and scanningelectron microscopy were used to identify structural alterations.At 2 h post dosing, the duodenal villi were markedly shortenedwhen compared to control duodenal villi. This erosion of thevilli throughout the duodenum caused massive exfoliation ofcolumnar and goblet cells, filling the lumen with cellular debrisand mucus. Disruption of the mucosal barrier resulted in con-tinuity between the intestinal lumen and lamina priopria of thevilli, with the loss of formed blood elements and lamina propriaconstituents into the intestinal lumen. The mucosal damage wasmuch more localized at 4 h post dosing, and the erosion of thevilli had been largely repaired. Repair was complete at 6 h postdosing.

Sodium RicinoleateGaginella et al. (1977a) studied the morphology of the colon

after perfusion of the organ with Sodium Ricinoleate solution,using 25 male New Zealand white rabbits. A Foley catheterwas inserted and the colon was perfused with control solution(1.25 ml per minute) for 20 min. The colon was then flushedand perfused with the test solutions. Ten rabbits were perfusedwith 10 mM Sodium Ricinoleate and the remaining three groupsof five were perfused with 2.5, 5.0, and 7.5 mM, respectively.The animals were killed and full thickness samples of colon



were obtained and prepared for light or scanning electron mi-croscopy. In additional experiments, tissue was obtained fromanimals that were not perfused and those perfused with controlbuffer (contained PEG 400) for 60 or 160 min.

Using scanning electron microscopy, mucous membranes ofcolons perfused with control buffer for 60 min and unperfusedcolons appeared normal. After 1 h of perfusion with 10 mMSodium Ricinoleate, patchy loss of epithelial cells was apparent.The loss of epithelial cells was confirmed using light microscopy.A dose response-relationship for mucosal damage was noted.The most severe damage resulted from perfusion with 10 mMSodium Ricinoleate. Lesser degrees of change and lesser areasof mucosal surface affected were associated with lower concen-trations. Small amounts of DNA (due to loss of DNA into thelumen) accumulated in the control buffer, and perfusion with 2.5mM Sodium Ricinoleate did not cause a significant increase inthese amounts. However, DNA accumulation increased signif-icantly after perfusion with 5.0, 7.5, and 10 mM Sodium Rici-nolete, and a plateau was reached with 7.5 mM solutions.

The control perfusate that was used contained low (PEG400) and high-molecular-weight (PEG 4000) polyethylene gly-cols. The absorption of PEG 400 increased progressively withincreases in the concentration of Sodium Ricinoleate (above2.5 mM) perfused. Sodium Ricinoleate (2.5 mM) did not in-crease absorption of the individual polymers that comprise PEG400 (molecular weight 242 to 594). The absorption of lowermolecular weight polymers (242 to 462) increased significantly(p < .005) in the presence of 5, 7.5, and 10 mM Sodium Ri-cinoleate. For higher molecular weight polymers (506 to 594),increased absorption in the presence of 5 mM Sodium Rici-noleate was not observed. However, significantly increased ab-sorption (p < .05) of the higher molecular weight polymerswas observed during perfusion with 7.5 and 10 mM SodiumRicinoleate (Gaginella et al. 1977a).

ComedogenicityCastor Oil

Fulton et al. (1976) evaluated the comedogenicity of cos-metics and cosmetic ingredients. Castor oil was applied to thebase of the internal right ear of each of three white albino rab-bits on Monday through Friday for 2 weeks. The left ear servedas the control. Comedogenicity was clinically evaluated on thefollowing Monday using the scale: 0 (no increase in visible hy-perkeratosis) to 5 (severe lesions, such as those seen followingthe application of coal tar). Six-millimeter punch biopsies (rightear) were obtained for microscopic examination, and comedo-genicity was evaluated according to the same scale. A score of1 (increase in visible hyperkeratosis extending to the possiblepresence of comedones) was reported for castor oil, which wasconsidered nonsignificant because repeated testing in differentrabbits often failed to produce identical effects.

In a study by Morris and Kwan (1983), the comedogenicityof castor oil was evaluated using three New Zealand rabbits.

Castor oil was applied to the external ear five times weekly (oneapplication per day). The actual amount applied ranged from 5to 10 mg/cm2. The animals were killed after the 14th applicationand several full-thickness sections of the test site and contralat-eral untreated ear were prepared for microscopic examination.Comedogenic activity was based on the degree of follicular hy-perkeratosis and other morphologic changes in the majority ofpilosebaceous units, when compared to control sections. Come-dogenicity was graded according to the following scale: 0 (neg-ative: pilosebaceous unit normal in appearance when comparedto control [untreated] ear section) to 5 (severe: widely dilatedfollicles, filled with packed keratin; follicular epithelial hyper-plasia causing partial or total involution of sebaceous glands andducts; possible inflammatory changes). Comedogenicity scoresfor castor oil were 0 to 1, corresponding to a slight increase inkeratin content within the follicle, with essentially no change infollicular epithelium.

Fulton (1989) evaluated the comedogenicity of castor oil(mixed in propylene glycol at 9:1 dilution; test concentration= 10%) using three New Zealand albino rabbits. The test sub-stance (1 ml) was applied onto the entire inner surface of one ear5 days per week for 2 weeks. Untreated ears served as controls.Follicular keratosis was evaluated both macroscopically (visu-ally) and microscopically, using a micrometer to measure thewidth of the follicular keratosis. Follicular keratosis was eval-uated according to the following scale: 0 or 1 (no significantincrease in follicular keratosis) to 4 or 5 (an extensive increasein follicular keratosis). The following scale was used to evaluateskin irritation that resulted from repeated application of the testsubstance: 0 (no irritation) to 5 (epidermal necrosis and slough).A follicular keratosis score of 1 and an irritation score of 0 wasreported for castor oil.

Skin SensitizationZinc Ricinoleate

International Bio-Research, Inc (1977b) conducted a skinsensitization study on Grillocin HY 77 (now TEGODEO HY77) using 30 white guinea pigs (average weight = 300 g).TEGODEO HY 77 (trade name mixture for Zinc Ricinoleate)has the following composition: Zinc Ricinoleate (more than50%), triethanolamine (10% to 25%), dipropylene glycol (1%to 5%), and lactic acid (1% to 5%) (Degussa 2001). Test andcontrol groups consisted of 20 and 10 guinea pigs, respectively.A closed patch containing the trade mixture (0.5 ml, undiluted)was placed on the left shoulder, clipped free of hair, of eachanimal and remained in place for 6 h. Treatments were repeatedonce weekly for 3 weeks.

At two weeks after the last exposure, test and control guineapigs were challenged (same procedure, right side) with dupli-cate closed patches. At 24 h post removal of the patches, the testsite on each animal was treated with a depilatory. Sites werethen rinsed and reactions were graded 2, 24, and 48 h lateraccording to the method of Draize. Clinical observations were


CASTOR OIL 59

normal throughout the study. Erythema and eschar formationwere graded according to the following scale: 0 (no erythema)to 4 (severe erythema [beet redness] to slight eschar formation[injuries in depth]). The following scale for edema formationwas used: 0 (no edema) to 4 (severe edema [raised more than1 mm and extending beyond area of exposure]). A score of 0(erythema and edema) was reported for each test and controlanimal during each of the three grading periods. Grillocyn HY77 did not produce a positive reaction in any of the test animals(International Bio-Research, Inc. 1977b).

AllergenicityHydrogenated Castor Oil

Lehrer et al. (1980) investigated the presence of castor beanallergens in Castor Wax (Hydrogenated Castor Oil) using bothin vitro and in vivo analyses. The experiments in this study in-volving human subjects are summarized under the subsectionAllergenicity in the Clinical Assessment of Safety section ofthis report. The following solvents were used to prepare aque-ous extracts of Castor Wax: phosphate buffered saline (PBS),urea-NaCl, Triton X-100, or sodium lauryl sulfate (SLS). Theaqueous extracts prepared were analyzed for total organic mat-ter and protein (expressed as percent of total organic matter ordry weight). Results from assays for protein in the aqueous ex-tracts of Castor Wax were as follows: 100% protein (urea-NaClextract), 17.0% (SLS extract), 12.9% (PBS extract), and 0.34%(Triton X-100 extract) protein.

In a qualitative precipitation analysis, Castor Wax aqueousextracts were analyzed for castor bean antigens using an im-munodiffusion procedure involving rabbit antiserum (50 µl ofantigen or antiserum in each well). The antiserum was producedin rabbits that had been immunized with extracts of castor beanin Freund’s complete adjuvant. Of the aqueous extracts tested,only the SLS Castor Wax extract reacted with the rabbit anti-sera. No reactivity with the antiserum was observed when theSLS solution alone was tested. Because the reaction was unusu-ally strong, suggesting a false-positive reaction, the extract wastested with normal rabbit serum. However, the same precipitinline was observed. It was concluded that the reaction of the SLSCastor Wax extract with rabbit serum proteins was probably anonspecific reaction.

The aqueous extracts of Castor Wax were also analyzed forallergens by determining their reactivity (48-h passive cutaneousanaphylaxis [PCA] reaction) with mouse anticastor reaginic (im-munoglobulin E [IgE]) antibody. CFW female mice were sen-sitized with reaginic antibody that was produced in BDF micethat had been immunized with heated castor bean extracts andBordetella pertussis adjuvant. The mice were challenged 48 hlater by intravenous injection of extracts of Castor Wax in 0.5%Evans blue solution and killed at 30 min post injection. Non-sensitized mice challenged with Castor Wax extracts served ascontrols. The reactions in control mice were always classifiedas negative. The antiserum did not react with PBS, urea-NaCl,

or Triton X-100 extracts of Castor Wax, but a positive response(positive PCA titer of 40, mean of three determinations) resultedfrom the reaction of the antiserum with the SLS extract of CastorWax.

The radioallergosorbent test (RAST) inhibition assay wasused for further analysis of allergens in the extracts of CastorWax. This assay was capable of detecting up to 7.5 µg castorallergen. Patient serum (100 µl) and Castor Wax extract (100 µl)were incubated with antigen-coated discs. Incubation was fol-lowed by the addition of radioiodinated anti-IgE and anotherincubation period. Normal serum incubated with antigen coateddiscs and test serum incubated with discs coated with a non–cross-reacting antigen served as controls. Assay results wereexpressed as percent inhibition of the patients’ RAS test. Nei-ther the PBS nor Triton X-100 extract of Castor Wax had aninhibitory effect on the RAS test, whereas the urea-NaCl extractinduced a small degree (13.4%) of inhibition. However, the SLSCastor Wax extract induced significant inhibition (40.1%) of theRAS reaction.

Based on the nonspecific reaction of the SLS Castor Waxextract with rabbit serum proteins in the first experiment of thisstudy, the authors examined the possibility that this extract mayinhibit the RAST nonspecifically using a heterologous RASTinhibition assay. An SLS or Triton X-100 extract of Castor Waxwas incubated with reaginic antisera from a patient who wassensitive to peanuts, and then assayed in the peanut RAST. TheSLS extract of Castor Wax inhibited the peanut RAST by 37%,suggesting that the results for the RAST inhibition assay in thepreceding paragraph may be due entirely or, in part, to a non-specific inhibition of the RAST reaction, rather than indicatingthat the SLS extract of Castor Wax contains specific castor al-lergens.

The results of these experiments (both in vitro and in vivo)indicate that allergens are present at low concentrations in CastorWax, because the SLS Castor Wax extract induced positive PCAreactions in mice and a positive direct RAS test for reaginiccastor allergens (Lehrer et al. 1980).

NEUROTOXICITYSodium Ricinoleate

Fox et al. (1983) applied Sodium Ricinoleate (0.01% to 1.0%)to the serosal surface of the rat (anesthetized male Sprague-Dawley rats, weights = 200 to 225 g) jejunum every 5 minfor 0.5 h. At 30 days post application, treated and untreatedjejunal segments were removed and examined microscopically.At a concentration of 0.1%, Sodium Ricinoleate significantlyreduced (p < .02) the number of ganglion cells in the myentericplexus. The highest test concentration (1% Sodium Ricinoleate)significantly reduced the number of cells in the myenteric plexus(p < .01) and the submucosal plexus (p < .02). The lowest testconcentration (0.01%) did not significantly reduce the numberof ganglion cells in the myenteric or submucosal plexus.



Renal ToxicityCastor Oil

Langer et al. (1968) evaluated effects of castor oil on the ratkidney, following intraluminal injection, using five male whitealbino rats (weights = 180 to 220 g). The kidney was exposedand proximal tubuli were punctured (using Leitz stereomicro-scope) and filled with castor oil. At 15 to 60 min, the proximaltubular segments (filled with oil) were fixed in situ. The kidneywas excised and prepared for both light and electron microscopicexamination. The injection of castor oil resulted in dilatation ofthe proximal convoluted tubular lumen and compression of thebrush border of proximal tubular cells, although a cessation ofthe normal pinocytosis was induced in the presence of tubularfluid. A toxic effect of castor oil on the tubular epithelium wasnot observed.

In a study by Racusen et al. (1986) evaluating the nephrotoxi-city of cyclosporine, castor oil served as the vehicle control. Twocontrol groups of eight adult male Munich-Wistar rats (weights= 220 to 270 g) were used. Group 1 vehicle controls (vehicle-ischemia group) underwent bilateral renal artery clamping, andwere then dosed intraperitoneally (i.p.) daily (4-day period) witha volume of castor oil vehicle that was equivalent to the i.p. doseof cyclosporine (dose = 60 mg/kg). Group 2 vehicle controls(vehicle-sham group) underwent sham surgery. The incisionswere closed prior to daily i.p. dosing with castor oil. On postop-erative day 3, feed was withdrawn and urine was collected over aperiod of 12 h for clearance studies. On postoperative day 4, theanimals were killed and tissues prepared for light and electronmicroscopy (confined to cortical proximal convoluted tubules).

In separate studies, renal blood flow and the glomerular fil-tration rate were determined. Two groups of eight saline controlgroups (saline-ischemia and saline-sham groups, respectively)were treated according to the same procedure.

Tubular vacuolization was a prominent feature in vehicle-ischemia control rats, and was observed to a minor degree in thevehicle-sham control rats. The clear vacuoles observed usinglight microscopy probably corresponded to two ultrastructuralchanges, dilated endoplasmic reticulum and lipid droplets. Withthe exception of the saline-sham group, dilated endoplasmicreticulum was observed in all control animals. However, lipiddroplets were not observed in any of the control animals. Thepresence of eosinophilic cytoplasmic inclusions was reported fortwo of eight vehicle-ischemia rats and four of eight vehicle-shamrats, but not for saline-control rats. Tubular necrosis (confinedentirely to outer medullary pars recta) was observed in half of thevehicle-ischemia rats and in all saline-ischemia rats, but was notobserved in saline-sham or vehicle-sham control groups. Tubularregeneration was noted in vehicle-ischemia and saline-ischemiacontrol rats.

The renal clearance study involved two control groups thatwere dosed with castor oil (five rats) or mineral oil (six rats). Two20-min inulin clearance determinations were made, and the vehi-cle was then administered i.p. (at dose volume comparable to 60

mg/kg cyclosporine dose; administered to test group of seven) ina region of the upper right abdomen. Dosing was followed by five20-min clearance periods. Compared to the mineral oil controlgroup (six rats), a significant decrease (25% decrease; p < .05)in renal blood flow was noted in rats (group of five) dosed i.p.with castor oil. Renal vascular resistance was also significantlyhigher (p < .05). No significant changes in inulin clearancewere reported. A significant decrease in blood pressure wasnoted in all groups; however, blood pressure remained withinthe physiologic and autoregulatory range (Racusen et al. 1986).

GENOTOXICITYCastor Oil

Zeiger et al. (1988) evaluated the mutagenicity of castor oil(United States Pharmacopeia purity grade; in dimethylsulfox-ide [DMSO]) in the preincubation assay using Salmonella ty-phimurium strains TA97, TA98, TA100, TA1535, and TA1537.The assay was conducted, with and without metabolic activation,according to a modification of the procedure by Haworth et al.(1983). Castor oil was tested at doses up to 10,000 µg/plateand classified as nonmutagenic (all strains, with and withoutmetabolic activation) over the range of doses tested in this as-say.

Hachiya (1987) evaluated the mutagenicity of castor oil usingS. typhimurium strains TA97, TA98, TA100, TA102, TA1537and strain WP2/pKM102 of Escherichia coli. In each strain,castor oil was tested at doses ranging from 100 to 5000 µg/platewith and without metabolic activation. Results were negative forall strains tested, both with and without metabolic activation.Cytotoxicity (at doses of 100 to 5000 µg/plate) was noted onlyin strain WP2/pKM102, with and without metabolic activation.

NTP (1992) reported a study in which groups of male andfemale B6C3F1 mice received diets containing 0.62%, 1.25%,2.5%, 5.0%, and 10% castor oil (in DMSO) for 13 weeks. Bloodsamples were obtained at the end of the 13-week study. Therewas no evidence of induction of micronuclei in peripheral ery-throcytes.

NTP (1992) also evaluated the induction of sister chromatidchanges by castor oil (in DMSO) in Chinese hamster ovary cells.The cells were incubated with castor oil at concentrations up to5000 µg/ml with and without metabolic activation. Mitomycin-C and cyclophosphamide served as positive controls withoutand with metabolic activation, respectively. DMSO served asthe solvent control. Castor oil did not induce sister chromatidexchanges either with or without metabolic activation.

Sodium RicinoleateIn a study by Haworth et al. (1983), the mutagenicity of

Sodium Ricinoleate was evaluated according to the preincu-bation procedure of the Salmonella assay (Ames et al. 1975)as described by Yahagi et al. (1975). Sodium Ricinoleate (indistilled water) was tested at concentrations up to 33 µg/plate


CASTOR OIL 61

at one testing laboratory, and up to 333.3 µg/plate at anotherlaboratory. The following S. typhimurium strains were usedwith and without metabolic activation: TA98, TA100, TA1535,and TA1537. Distilled water served as the vehicle control. Thepositive controls were as follows: 2-aminoanthracene, 4-nitro-o-phenylenediamine, sodium azide, and 9-aminoacridine. Re-sults for Sodium Ricinoleate were negative with and withoutmetabolic activation.

DNA Binding of Reaction ProductMethyl Ricinoleate

Frankel et al. (1987) evaluated the fluorescence formed by theinteraction of DNA with lipid oxidation products. The keto ester,methyl ketoricinoleate, was prepared from Methyl Ricinoleateby allylic oxidation with a CrO3-pyridine complex in methylenechloride. Results from this assay indicated that methyl ketori-cinoleate (relative concentration = 1 mM/3 ml) produced verylittle fluorescence (mean = 29 ± 2 units) with DNA in the pres-ence of ferric chloride–ascorbic acid. The mean value for methyllinolenate hydroperoxides (used as reference) was 362 ± 9 units.Mean values were given as the fluorescence intensity of DNAafter 72 h (excitation: 315 nm; emission: 420 nm).

CARCINOGENICITYRicinoleic Acid

In a study by Boyland et al. (1966), 2% Ricinoleic Acid,in gum tragacanth, was injected intravaginally into each of 20BALB/c female mice (5 to 6 weeks old). Injections were madetwice per week, and each animal received a total of 100 in-jections. According to the same dosing schedule, each of 20positive control and 30 vehicle control mice received 62 injec-tions of 0.3% dimethylbenz(a)anthracene and 100 injections ofgum tragacanth, respectively. An additional 30 mice served asthe untreated control group.

None of the 20 mice injected with Ricinoleic Acid had neo-plasms or hyperplastic lesions of the corpus uteri, cervix uteri,vagina, or perineal skin. However, benign lung adenomas wereobserved in ten of the 13 mice dosed with Ricinoleic Acid andin 6 of the 24 vehicle control mice that were killed after the 14thmonth of dosing. Benign lung adenomas were also observedin 9 of the 20 untreated control mice that were killed after the14th month. The difference in benign adenoma incidence be-tween Ricinoleic Acid–treated and untreated control mice wasnot statistically significant (p > .1). Additionally, comparedto controls, there was no tendency for Ricinoleic Acid–treatedmice with adenomas to have a higher average number of tumornodules per mouse. Malignant tumors of the vagina and perinealskin were observed in 15 of the 20 (75%) positive control mice.The authors stated that the results of this study do not provideany definite evidence of the carcinogenicity of Ricinoleic Acid(Boyland et al. 1966).

Tumor Promotion ActivityCastor Oil, Ricinoleic Acid, and Glyceryl Ricinoleate

Shubik (1950) evaluated the tumor promotion activity of cas-tor oil, Ricinoleic Acid, Glyceryl Ricinoleate and the followingother chemicals using groups of mice (strain and weights notstated): 20% turpentine in liquid paraffin, 0.3% acridine in liq-uid paraffin, 0.5% fluorene in liquid paraffin, 1% phenanthrenein liquid paraffin, silver nitrate (10% aqueous), and oleic acid.Castor oil, Ricinoleic Acid, Glyceryl Ricinoleate, and oleic acidwere not diluted prior to testing.

Initially, the nine substances were tested using groups of threemice (one group per substance). The test substances were ap-plied to a small area of skin in the interscapular region (clippedfree of hair). Four applications per mouse, spaced over a periodof 2 weeks, were made. At the end of the application period,the animals were killed and tissues were obtained for micro-scopic examination. The following substances induced slightepidermal hyperplasia: castor oil, Ricinoleic Acid, Glyceryl Ri-cinoleate, oleic acid, fluorene, and phenanthrene. Turpentine in-duced minimal histologic change, and acridine induced markedepidermal hyperplasia. Silver nitrate induced hyperplasia mostmarked in the hair follicles.

In the tumor promotion experiment (groups of 10 mice; strainand weights not stated), each mouse received a single applicationof 9,10-dimethyl-1,2-benzanthracene in liquid paraffin. The ninetest substances (one per group) were then applied semiweeklyfor 20 weeks. For all groups of mice tested, no tumors wererecorded. Castor oil, Ricinoleic Acid, and Glyceryl Ricinoleate,as well as the other test substances that were evaluated, were nottumor promoters in this study (Shubik 1950).

Ricinoleic AcidBull et al. (1988) investigated the effect of Ricinoleic Acid

(unoxidized) on DNA synthesis and the induction of ornithinedecarboxylase activity. The authors noted that unsaturated fattyacids are readily oxidized to a variety of biologically activederivatives, and have suggested that autoxidation products ofpolyunsaturated fatty acids may also play a role in the enhance-ment of tumorigenesis. They noted that this suggestion is basedon published results (Bull et al. 1984) indicating that hydroper-oxy and hydroxy derivatives of arachidonic acid and linoleicacids, the primary autoxidation products of major dietary unsat-urated fatty acids, induce ornithine decarboxylase (ODC) andstimulate DNA synthesis (two components of mitogenesis) incolonic mucosa in vivo.

Male Sprague-Dawley rats (weights = 100 to 125 g) fedthe following semisynthetic diet (weight percentages indicated)were starved for 24 h prior to intrarectal (i.r.) instillation of Rici-noleic Acid (vehicle: 5% ethanol in 50 mM NaHCO3, pH 8.0):casein (20%), DL-methionine (0.2%), salt mix (3.6%), vitaminmix (2%), beef fat (5%), dextrose (45.2%), cellulose (5%), andcornstarch (19%). Two experiments were performed using Ri-cinoleic Acid test concentrations of 5 and 10 mM. Test groups



consisted of three to five rats per dose level. The vehicle controlgroup (three rats per experiment) was dosed with 5% ethanol in50 mM NaHCO3, and positive control animals received 6 mMdeoxycholate. Data were presented as an average of the two ex-periments. The measurement of DNA synthesis in the colon wasbased on the incorporation of [3H]dThd 12 h after i.r. instilla-tion of Ricinoleic Acid. ODC activity was determined in colonicmucosa that was harvested 3 h after i.r. instillation of RicinoleicAcid.

Ricinoleic Acid was inactive as a stimulator of DNA synthesisand inducer of ODC activity in the rat colon. Concentrationsup to 10 mM resulted in insignificant increases in [3H]dThdincorporation and did not increase the level of ODC activityabove control values (Bull et al. 1988).

Anticancer ActivityExtract of Castor Oil

Xie et al. (1992) evaluated the anticancer/antitumor activityof an extract of castor oil using male Kunming mice (weights= 18 to 22 g) and mice bearing S180 ARS ascitic fluid tumorcells. Castor oil was saponified and acidified to obtain a coarse,fatty acid mixture that was recrystallized and refined to producethe active anticancer component. Using Tween-80 (Polysorbate80), an emulsion containing this component was produced. Apolyphase liposome from castor oil extract was also produced.The inhibitory action of the anticancer component on S180 tumorcells was evaluated. Ascites was obtained from mice that hadbeen inoculated with S180 tumor cells (with well-grown ascites)that had been washed with physiological brine in order to collectthe cancer cells. The physiological brine was diluted and injected(2 ml) subcutaneously into the right front axilla of each mouse.On the day after injection of the tumor cells, the mice wererandomly divided into groups.

The three dilution control groups (8 to 10 mice per group)were injected with 200, 300, or 400 mg/kg of a physiologi-cal brine solution containing an equal load of Tween-80. Thefour polyphase liposome control groups (eight mice per group)were injected with blank liposomes (doses of 300, 300, 400, and400 mg/kg, respectively). For dilution control and polyphase li-posome control groups, injections were made into the abdominalcavity daily for 7 days, after which the mice were killed. Subcu-taneous tumors were removed and weighed in order to calculatethe tumor suppression rate (%).

Tumor suppression rates for dilution controls were as fol-lows: 30.6% (200 mg/kg dose group), 37% (300 mg/kg dosegroup), and 53.1% (400 mg/kg dose group). The following tu-mor suppression rates were reported for the polyphase liposomecontrol groups: 40.2% (300 mg/kg dose group), 36.4% (the other300 mg/kg dose group), 55.7% (400 mg/kg dose group), and58% (the other 400 mg/kg dose group).

In another experiment, the inhibitory action of the anticancercomponent extracted from castor oil on ARS ascites cancer wasevaluated according to a similar procedure. Ascites was obtained

from mice inoculated with ARS cancer cells (with well-grownascites) that had been washed with physiological brine in orderto collect the cancer cells. The physiological brine was dilutedand injected (0.2 ml) into the abdominal cavity of each mouse.On the day after injection of the cancer cells, each of nine micewas injected with a polyphase liposome that was produced fromcastor oil extract (dose = 200 mg/kg) daily for 7 days. At theend of the treatment period, the animals were monitored (forsurvival) for an additional 35 days.

Study results indicate that the castor oil extract had a strongsuppressive effect on S180body tumors in mice. Its suppressiveeffect on ARS ascites cancer was also very strong, with 64% ofthe ascites tumors in mice being completely cured. Compared tocontrols, the life extension rate was more than 136% (p < .0012)(Xie et al. 1992).

REPRODUCTIVE AND DEVELOPMENTAL TOXICITYCastor Oil

NTP (1992) (see earlier Subchronic Oral Toxicity section)fed groups of rats and mice diets containing 0.62%, 1.25%,2.5%, 5.0%, and 10% castor oil, respectively, continuouslyfor 13 weeks. A slight decrease in epididymal weight (6% to7%) was observed in mid- and high-dose groups of male rats;however, this finding was not dose related. No effects on anyother male reproductive end point (testes weight and epididy-mal sperm motility, density, or testicular spermatid head count)or female reproductive endpoint (estrous cycle length, or timespent in each phase of the cycle) were noted. Microscopically,there were no treatment-related lesions in any organ or tissue.These results indicate that there was little or no evidence of anyreproductive toxicity in rats that was associated with castor oil inthe diet. For male and female mice, castor oil in the diet had noadverse effects on any male or female reproductive parameter.

Litvinova and Fedorchenko (1994) evaluated the influence ofsingle doses of different plant oils on the estrous cycle and fer-tility using female Wistar rats (number and weights not stated).Castor oil (0.2 ml, single dose) was injected intramuscularly onthe first day after estrus. Study of the estrous cycle was based onthe following: the cytologic picture that was obtained from vagi-nal smears, the phase structure (proestrus, estrus, metaestrus, anddiestrus) of the cycle, and the frequency of estrus over a 15-dayobservation period prior to injection of castor oil (control) anda similar length of time after injection (test). Fertility was stud-ied using intact animals (control) and animals that were treatedwith castor oil. On day 2, after castor oil injection (i.e., duringdiestrus), the females were mated with male rats. Control fe-males were also mated with male rats on day 2. The first dayof pregnancy was defined by the presence of spermatozoa invaginal smears. Pregnant females were killed on day 20. The es-trous cycle phases were recorded 3 to 4 times during the 15-dayobservation period.

The injection of castor oil resulted in a reduction in thefrequency of estrus by a factor of 1.4 and lengthening of the


CASTOR OIL 63

interestrous phase by 39.6%. The authors concluded that thelatter finding may be indicative of prolongation of luteolyticprocesses and an inhibition of folliculogenesis.

In female fertility experiments, mating occurred over a pe-riod of 3.22 ± 0.12 days. The index of fertility was calculatedfrom the ratio of the number of mated females to the totalnumber of females in the test. The fertility index for intact an-imals (control) was 100%, and pregnancy occurred in 100%of the cases. A decrease in the pregnancy index was reportedfor female rats injected intramuscularly with castor oil; how-ever, no reliable difference between test and control values wasdetected.

Compared to controls, castor oil also caused a reduction inthe number of corpora lutea in the ovaries, and this observa-tion was said to have been a consequence of the suppression offolliculogenesis and ovulation. Additionally, the number of im-plantation sites in uteri from female rats injected with castor oilwas decreased when compared to control rats. A decrease in thenumber of live fetuses in uteri and an increase in pre- and postim-plantation deaths was also observed in rats injected with castoroil. The authors concluded that castor oil, injected intramus-cularly, suppressed ovarian folliculogenesis and also had anti-implantation and abortive effects (Litvinova and Fedorchenko1994).

Castor oil served as the vehicle control in a study evaluatingthe effect of long-term treatment with ICI 182,780 (an antie-strogen) on the rat testis (Oliveira et al. 2001). Two groups offour male, 30-day-old Sprague-Dawley rats served as vehiclecontrols. In one control group, castor oil (0.2 ml) was injectedsubcutaneously once per week, and the animals were killed 100days after the first injection. The second group was dosed accord-ing to the same procedure; animals were killed 150 days after thefirst injection. The experiment was extended to 150 days (group2 rats), based on results for group 1 ICI-treated and control ani-mals on day 100.

Specifically, Group 1 ICI-treated rat testes were significantlyheavier (35% heavier, p < .05) than those of the control group,and a significant increase in diameter and luminal areas of thesemineferous tubules was observed. Additionally, in group 1ICI-treated and control rats, spermatogenesis appeared normaland there was no evidence of degeneration or sloughing of germcells.

On day 150, a 33% decrease (compared to day 100 results forICI-treated rats; p = .065) in mean testicular weight was notedin ICI-treated rats. Seventy-five percent of the testes weighedless than the mean control value of 1.71 g. Atrophy of the sem-ineferous tubules was observed in all but one of the testes ofICI-treated rats. Additionally, the rete testis and efferent ductulelumens in all ICI-treated rats were greatly dilated, compared tothose of controls.

During the treatment period, mating studies were performedto compare the fertility of ICI-treated and control rats on days45, 73, 100, 125, and 150. Males were housed individually withtwo adult females for a 15-day period. Through 100 days of

treatment, there was no difference in male reproductive perfor-mance between ICI-treated and control rats. However, after day100, 100% fertility was maintained in control males, but, by day150, fertility had decreased to 25% in ICI-treated males (Oliveiraet al. 2001).

Extract of Ricinus communis SeedsThe following study is included because castor oil may be

extracted from the bean of the tropical plant, Ricinus communisby a method that involves the use of a solvent.

Okwuasaba et al. (1991) evaluated anticonceptive and es-trogenic effects of a methanol extract of Ricinus communisvar.minor seeds (ether-soluble fraction) using the following an-imals (groups of 10): adult albino Wistar rats (weights = 160 to210 g), young albino Wistar rats (weights = 40 to 60 g), imma-ture Swiss albino female mice (21 to 23 days old; weights = 10to 13 g), and adult female New Zealand white rabbits (2.5 to 3.0kg).

In the antifertility experiment, adult female rats and rabbitswith regular estrus cycles were used. The females were matedovernight (3:1 female/male ratio), and the day of mating wasconsidered day 0. Castor bean extract was injected subcuta-neously (s.c. dose of 0.6 or 1.2 g/kg) into female rats once dailyfor two days, and mating occurred on the third day. Femalerabbits were injected intramuscularly with Castor bean extract(dose = 200 mg/kg). Control animals were injected s.c. withcorn oil for two consecutive days. A laparotomy was performedto confirm that implantation had occurred.

Castor bean extract (0.6 or 1.2 g/kg dose) prevented nida-tion in rats, and none of the treated rats delivered pups atterm. The results for rabbits (200 mg/kg dose) paralleled thosefor rats. Nidation was prevented, and the extract protectedthe rabbits against pregnancy for over three gestation periods(i.e., 110 to 120 days). The normal gestation period for rab-bits is 28 to 30 days. Effects induced by Castor bean extractwere reversible in rats and rabbits. No fetal abnormalities wereobserved.

In the study to determine estrogenic activity, the followingendpoints were used to estimate the estrogenicity of the Castorbean extract: uterine weight ratio, degree of vaginal cornifica-tion, and quantal vaginal opening. In one experiment, groupsof 10 Swiss albino female mice (21 to 23 days old; weights= 10 to 13 g) were injected s.c. with 1.0 or 4.0 mg/kg Castorbean extract (in corn oil, 0.2 ml) daily for 4 days. In a similarexperiment, bilateral ovariectomy was performed on young, im-mature rats (groups of five), and the wound was sutured. Aftera 15-day recovery period, the groups of rats were injected s.c.with 0.6 or 1.2 g/kg Castor bean extract (in corn oil, 0.2 ml)daily for 4 days. In both experiments, suitable controls (injecteds.c. with corn oil only) were maintained. Additionally, estradiol-17β (reference hormone; dose = 10 µg/kg) was administeredto rats (group of 10) and mice (group of 10). Mice and rats werenecropsied 24 h after the last injection. Body and uterine wetweights were recorded.



Results for bilaterally ovariectomized rats indicated thatdoses of 0.6 and 1.2 g/kg induced increases in relative uter-ine weight of 116.7 ± 6.5 (p < .01) and 211.6 ± 8.2 mg/100 gbody weight (p < .001), respectively, compared to a controlvalue of 83.3 mg/100 g body weight. Compared to rats, Castorbean extract (1.0 and 4.0 mg/kg) induced a qualitatively similareffect in immature mice. In rats and mice, the effect on relativeuterine weight appeared to have been dose-dependent. Estradiol-17β also increased uterine weight in rats and mice. The relativeuterine weights (mg/100 g body weight) for rats and mice dosedwith estradiol-17β were reported as follows: 309.2 ± 11.4 (rats)and 517.5 ± 12.3 (mice).

Cornification of the vaginal epithelium and quantal open-ing of the vagina were noted in immature mice and bilaterallyovariectomized rats (both dose groups for each). A dose-relateddecrease in the number of leukocytes and increases in cornifiedand epithelial cell counts were also reported for both species.No significant changes in body weight were observed.

The authors concluded that the ether-soluble portion of themethanol extract of Ricinus communis var. minor seeds pos-sesses anti-implantation, anticonceptive, and estrogenic activityin rats and mice when administered subcutaneously (Okwuasabaet al. 1991).


Metabolism and ExcretionCastor Oil

Watson et al. (1963) studied the absorption and excretionof castor oil in five subjects (ages and weights not stated). Thecomposition of the castor oil was as follows: palmitic acid (1%),palmitoleic acid (0.1%), stearic acid (1%), oleic acid (3.2%),linoleic acid (4.7%), and Ricinoleic Acid (90%). The castor oil(of medicinal purity) contained a trace amount of oil labelledwith 131I, and the doses administered ranged from 4 to 60 g(approximately 6 µCi of radioactivity per dose). Castor oil wasadministered to the five hypertensive patients on the day before ascheduled intravenous pyelogram; thereafter, only a light mealof coffee and toast was allowed. Stool collections were madeduring the first 24 h after dosing and during the subsequent 72 h.Urine was collected in 24-h samples. Small doses of oil wereadministered to the three normal volunteers, and free diet wasallowed. Stools were collected at 2 and 3 days after dosing.

Fecal recovery of 131I (%) ranged from 11.4% (for 10 g doseof castor oil) to 86.0% (for 44.4 g dose of castor oil). The authorsconcluded that castor oil can be absorbed by human subjects, thatabsorption is inversely related to the administered dose, and, atsmall doses (4 g), that absorption is virtually complete (Watsonet al. 1963).

Hagenfeldt et al. (1986) administered castor oil (10 to 15 ml)orally to three healthy subjects. Urine was collected between2 and 8 h post dosing. The following three epoxydicarboxylicacids were excreted in the urine: 3,6-epoxyoctanedioic acid;

3,6-epoxydecanedioic acid; and 3,6-epoxydodecanedioic acid.These three Ricinoleic Acid metabolites were also detected inthe urine of rats as described earlier.

Induction of LaborCastor Oil

Davis (1984) investigated the use of castor oil to stimulatelabor using 196 patients with premature rupture of membranes(PROM), at least 4 h in duration, who were between 37 and42 weeks of gestation. Patients were identified by reviewingcharts of all patients who were admitted at an out-of-hospitalbirthing center from 1976 through 1981. Of the 196 patients, 107(mean age = 28.6 years) were dosed orally with castor oil (2 oz)and 89 (mean age=27.6 years) were not. Castor oil was adminis-tered only to PROM patients who had a latency period of at least 4h. All patients were observed for labor onset for 24 h after the on-set of PROM. If labor did not occur at this time, the patients weretransferred to a hospital for oxytocin stimulation. The longestinterval between rupture of the membranes and delivery was48 h.

Of the 107 patients dosed with castor oil, 80 (75%) had laboronset. Spontaneous labor occurred in 52 (58%) of the 89 controlpatients. This difference between patients dosed with castor oiland controls was statistically significant (p < .05). The intervalbetween castor oil administration and the onset of labor rangedfrom 1 to 13 h (mean = 4 h).

Labor outcomes were also evaluated for type of delivery, in-cidence of oxytocin stimulation, and infant well-being. The needfor cesarean sections was nearly three times greater in the controlgroup (15.7% incidence) than in patients dosed with castor oil(5.6% incidence). This difference was found to be statisticallysignificant (p < .01). Additionally, the group dosed with castoroil did not require oxytocin stimulation as frequently (36% in-cidence) when compared to the control group (43% incidence),and the difference was not statistically significant.

Infant outcomes in the two groups were studied by observingApgar scores at 1 and 5 min, and looking for any evidence ofmeconium staining. Two infants with Apgar scores of <7 werereported for both groups. At the time of membrane rupture, thepresence of meconium was very low in both groups. Meconiumstaining was not observed after dosing with castor oil. It is alsoimportant to note that there were no maternal deaths and no sig-nificant maternal morbidity. The authors concluded that castoroil can be used safely and effectively to stimulate labor (Davis1984).

In a study by Mitri et al. (1987), the amniotic fluid wasexamined at the time of rupture of membranes in 478 of the498 women in labor. The amniotic fluid was meconium-stainedin 174 subjects (mean age = 28.5 ± 0.65 years) and clear inthe remaining 304 subjects (mean age = 25.9 ± 0.37 years).Cesarean section, low Apgar score, and the recent ingestionof castor oil were significantly more common in subjects withmeconium-stained amniotic fluid. The authors concluded that


CASTOR OIL 65

the passage of fetal meconium was predictive of poor labor out-come in terms of Apgar scores and the need for cesarean section.It was recommended that women who take castor oil in late preg-nancy should be identified as a high-risk group for the passageof fetal meconium.

In a case report by Steingrub et al. (1988), a 33-year-oldpregnant female (at week 40 of gestation) ingested castor oil toinduce labor. Within 60 min of ingestion, cardiopulmonary arrestoccurred and was reportedly due to amniotic fluid embolism.

Garry et al. (2000) evaluated the use of castor oil to inducelabor in 52 pregnant women (mean age = 24.8 ± 6.7 years)at Saint Mary’s Hospital in Brooklyn, New York. The untreatedcontrol group consisted of 48 pregnant women (mean age = 24.4± 4.9 years). The two groups of women did not differ in mater-nal age, parity, or gestational age. Castor oil was administeredas a 60-ml dose in orange or apple juice, and its use was deemedsuccessful only if active labor began within 24 h. Labor wasdefined as one or more contractions every 5 min, with cervi-cal dilatation of 4 cm or more. Active labor was induced in 30(57.7%) of the 52 women dosed with castor oil, compared to 2of the 48 women in the control group (p < .001). The cesareansection rate for women dosed with castor oil was 19.2% (10 of52 women), compared to 8.3% (4 of 48 controls) in the untreatedcontrol group. No relationship between dosing with castor oil,birth weight, and mode of delivery (p = .66) was found. Ad-ditionally, no adverse outcomes for the mother or fetus wereidentified. The authors concluded that women dosed with castoroil had an increased likelihood of initiation of labor within 24 h,compared to women who were not dosed with castor oil.

Ocular IrritationCastor Oil

In a study by Secchi et al. (1990), a double-masked clinicaltrial was performed using a group of nine patients (ages notstated) with vernal keratoconjunctivitis. One eye was treatedwith 2% cyclosporine in castor oil four times daily for 15 days.The other eye was treated with castor oil solution only accordingto the same procedure. Mild and transient discomfort and minorepithelial changes were observed in both eyes.

In another clinical study (Gluud et al. 1981), vital stainingwas used to investigate the eyes of 100 patients (ages not stated)following the instillation of castor oil and the eyes of 50 patientsfollowing the instillation of 0.9% saline. One drop (0.01 ml)of sterile fluorescein–rose bengal (RB) dye mixture was in-stilled into the lower conjunctival sac and the ocular mucosawas examined using a slit lamp. White light was used to exam-ine RB-stained spots and cobalt blue light was used to examinefluorescein-stained spots. The ocular mucosa was divided intofive regions, and the number of stained spots in each region wascounted/estimated and graded. The authors concluded that cas-tor oil affected the cornea and conjunctiva, i.e, degeneration anddeath of epithelial cells (stained with RB) and continuity breaksin the epithelium (stained with fluorescein).

Skin Irritation/Dermal ToxicityCastor Oil

Motoyoshi et al. (1979) evaluated the skin irritation poten-tial of undiluted castor oil using 50 adult male volunteers (agesnot stated). Individuals with known allergic reactions were ex-cluded. Patches containing 0.05 g of the test material were ap-plied to skin of the back and remained for 48 h. At the end ofthe application period, test sites were swabbed with dry gauzeto remove any residual test material and reactions were scored30 minutes later according to the following scale: − (negativereading) to + + ++ (bullous reaction). Castor oil was mildlyirritating to the skin of human subjects.

In a study by Meyer et al. (1976), undiluted castor oil wasapplied to test fields delineated on the right thigh of each of threemale subjects (22 to 31 years old). The control field was locatedon the opposite side. According to the test procedure, castor oilwas rubbed onto the skin gently (<30 s) on 10 sucessive days.The control field was massaged only. A tissue section (1 × 1cm) was excised from the center of each test field and five toeight sections (7 µm in thickness) per test area were subjected tomicroscopic examination. Macroscopic skin changes were notobserved in either of the three subjects.

At microscopic examination, clear hyperchromasia and anincrease in the number of cells were observed in the basal celllayer. Slight widening of the granular cell layer was also noted(Meyer et al. 1976).

Hydrogenated Castor OilIn a study by de Groot (1994), members of the Dutch Contact

Dermatitis Group and nonmember dermatologists patch tested 1to 20 patients (ages not stated) either suffering from or suspectedof suffering from contact allergy to cosmetic products. Detailsregarding the patch test procedure were not included. Patch testresults indicated no reactions to 30% Hydrogenated Castor Oilin petrolatum.

Ethyl RicinoleateThe skin irritation potential of 20% Ethyl Ricinoleate in

petrolatum was evaluated using 32 healthy male volunteers (agesnot stated) in a 48-h closed patch test. Skin irritation was not ob-served (RIFM 2000).

Allergenicity

Predictive TestsEthyl Ricinoleate

The skin sensitization potential of 20% Ethyl Ricinoleate inpetrolatum was evaluated using 32 healthy male volunteers inthe maximization test. The test substance was applied (underocclusion) to the same site on the forearms of each subject forfive alternate-day 48-h periods. Each test site was pretreated with5% aqueous sodium lauryl sulfate (under occlusion) for 24 h.At the end of a 10- to 14-day nontreatment period, challenge



patches were applied (under occlusion) to new test sites for 48h. Challenge applications were preceded by 30-min applicationsof 2% aqueous sodium lauryl sulfate (under occlusion) on theleft side. On the right side, the challenge application was notpreceeded by treatment with sodium lauryl sulfate. A fifth site(challenge with petrolatum) served as the control. Reactionsclassified as either significantly irritating or allergic were notobserved (RIFM 2000).

Provocative TestsCastor Oil

Fujimoto et al. (1997) conducted a study involving 332patients (25 males, 307 females; ages ≈20 to 70) suspectedof having cosmetic contact dermatitis. The subjects werepatch-tested with numerous cosmetic products and cosmetic in-gredients. Patch tests (Finn chambers) were applied to the backfor 48 h, and the test sites were examined at 30 minutes afterpatch removal, 1 day later, and 4 to 5 days after patch removal.None of the 49 patients patch-tested with castor oil had a positivereaction.

In a study by Hino et al. (2000), 346 patients (31 males, 315females; ages ≈ 20 to 70 years) suspected of having cosmeticdermatitis were patch tested with various cosmetic products andcosmetic ingredients. Patch tests (Finn chambers) were appliedto the back for 48 h. Test sites were examined according to theschedule in the preceding study. Of the 76 patients patch-testedwith castor oil, one had a positive reaction. This reaction wasobserved only during the second reading (i.e., the day after the30-min reading).

Hydrogenated Castor OilLehrer et al. (1980) evaluated the sensitivity of three human

subjects (with occupational hypersensitivity to castor allergens)to castor bean extract and four Castor Wax extracts (solvent =SLS, PBS, urea-NaCl, or Triton X-100). Seven normal labora-tory personnel served as controls. The test substances were ap-plied to the skin using both patch and prick tests. Only the castorbean extract and the SLS extract of Castor Wax were evaluatedin the prick test, and the four Castor Wax extracts were evalu-ated in the patch test. In the prick test (to detect IgE-mediatedhypersensitivity), a drop of allergen extract was applied to theskin. Following application to the skin, the underlying superficiallayer of the skin was pricked with a 25-gauge needle. Reactionswere scored 15 min after application of the allergen. A positiveprick test reaction was defined as a wheal and flare reaction withedema >5 mm. Castor bean extract was tested at concentrationsup to 1000 µg/ml and, SLS Castor Wax extract, at concentra-tions up to 22,000 µg/ml. Results from the prick test indicatedno immediate skin reactivity to castor bean extract or the SLSCastor Wax extract.

In patch tests (to detect cell-mediated hypersensitivity), asemiocclusive patch containing either of the four Castor Waxextracts (concentration not stated) or paraffin (control) was ap-

plied to the skin for 24 and 48 h. Reactions were scored at 24and 48 h post removal.

The three patients were highly sensitive to castor allergen inthe prick test (positive skin reaction to 1.0 or 0.1 µg/ml castorbean extract). The patients also had a positive skin reaction to theSLS Castor Wax extract, where the level of sensitivity was 100-to 100,000-fold less than that induced by castor bean extract.None of the seven normal subjects had a delayed reaction toany of the four Castor Wax extracts that were tested. Prick testresults (normal subjects) indicated no immediate skin reactivityto castor bean extract or the SLS Castor Wax extract.

Because immediate hypersensitivity to Castor Wax was ob-served in the three patients who were sensitive to castor bean, ad-ditional tests (prick tests) were performed to determine whetherCastor Wax solubilized in different organic solvents or an un-derarm deodorant stick containing Castor Wax would induceirritation and elicit a positive immediate hypersensitivity reac-tion in these three patients. Positive skin reactions to Castor Wax(in different solvents or in a deodorant stick) were not detected.

The four Castor Wax extracts and paraffin (control) wereevaluated in patch tests for cell-mediated hypersensitivity. Noneof the three patients had a delayed reaction to any of the fourCastor Wax extracts (test concentration not stated).

The positive skin reactions (immediate skin reactivity) insensitized individuals, together with the positive PCA reactionsin mice and positive direct RAST for reaginic castor allergens(summarized earlier in this report) that were induced by SLSCastor Wax extract, indicate that allergens are present in CastorWax at low concentrations.

A direct RAS study was conducted to determine whether theSLS extract of Castor Wax contains specific antigens or non-specifically inhibits the RAS assay. Discs were coated with cas-tor bean extract or the SLS Castor Wax extract and a direct RASassay was performed using serum from one patient who was sen-sitive to castor allergens, a patient who was sensitive to peanuts,or pooled human serum (control). The patient sensitive to castorallergens had a significant RAS test ratio of 18.87 to castor beanallergen and a significant RAS test ratio of 8.04 to SLS CastorWax extract. The patient sensitive to peanuts did not have a sig-nificant RAS test to either castor bean extract or the Castor Waxextract. The results from this direct RAS study indicate that SLSCastor Wax extract does contain Castor bean allergens, althoughthe SLS Castor Wax extract can nonspecifically inhibit the RASassay (Lehrer et al. 1980).

Ricinoleic AcidIn a retrospective study by Lim and Goh (2000), 202 consec-

utive patients (182 females, 20 males) with eczematous cheili-tis who attended a contact and occupational dermatoses clinicin Singapore between January of 1996 and December of 1999were patch-tested. Mean ages for female and male patients were31.1 and 28.8 years, respectively. Patch tests were conductedaccording to International Contact Dermatitis Research Group(ICDRG) recommendations. Twenty-nine patients (2 males,


CASTOR OIL 67

27 females) had positive reactions to Ricinoleic Acid. Of the29 reactions, 22 were considered relevant positives.

Allergenicity/PhotoallergenicityCastor Oil

In a study by Hashimoto et al. (1990), 103 patients (ages notstated) suspected of having cosmetic-related contact dermati-tis were patch tested with castor oil (as is). Both patch testsand photopatch tests were conducted according to ICDRG basicstandards. The patch test units consisted of a combined use ofboth Finn chambers and Scanpor tape. One patient had a posi-tive patch test reaction to castor oil. No positive photopatch testreactions were reported.

Case ReportsCase reports involving Castor Oil and Ricinoleic Acid esters

are summarized in Table 6.

Occupational ExposureGohte et al. (1983) conducted a study involving 28 persons

(14 men, 14 women; age range = 17 to 65 years) who were em-ployed by a company involved with importing, preparing, anddistributing plant products that are used in spices and as ingre-dients of health foods. The period of employment varied fromtwo months to 20 years, and 25 of the 28 were smokers. Thir-teen of the 28 developed the following work-related symptoms:rhinitis, conjunctivitis, asthma, itch, or urticaria. Blood samplesfrom 25 subjects were subjected to IgE analysis using PhadebasIgE PRIST (paper radioimmunosorbent test). Phadebas RAST(radioallergosorbent test) was performed on 25 persons againstantigens from an extract of castor oil bean. Fifteen subjects wereprick-tested and 14 were patch-tested with an extract of castoroil bean. Of the three tests, only the RAST test yielded positiveresults; 1 of 25 subjects had an allergic reaction to an extractof castor oil bean. None of the subjects without work-relatedsymptoms had positive reactions.

SUMMARYRicinus Communis (Castor) Seed Oil, Ricinoleic Acid,

Glyceryl Ricinoleate, Glyceryl Ricinoleate SE, Potassium Ri-cinoleate, Sodium Ricinoleate, Zinc Ricinoleate, Cetyl Rici-noleate, Ethyl Ricinoleate, Glycol Ricinoleate, Isopropyl Ri-cinoleate, Methyl Ricinoleate, and Octyldodecyl Ricinoleatefunction, in cosmetics, as skin-conditioning agents, emulsionstabilizers, and surfactants. Ricinus Communis (Castor) SeedOil also functions as a fragrance and Hydrogenated Castor Oilalso functions as a viscosity-increasing agent—nonaqueous. Inthe case of Zinc Ricinoleate, functions include deodorant agent,opacifying agent, and anticaking agent.

Ricinoleic Acid accounts for 87% to 90% of the fatty acylgroups of Ricinus Communis (Castor) Seed Oil and the follow-ing other fatty acids comprise the remaining fatty acyl groups:

oleic acid (2% to 7%), linoleic acid (3% to 5%), palmitic acid(1% to 2%), stearic acid (1%), dihydrostearic acid (1%), andtrace amounts of other fatty acyl groups.

Hydrogenated Castor Oil consists primarily of glyceryl-trihydroxystearate. The National Formulary has the followingrequirements for Hydrogenated Castor Oil: free fatty acids (freefatty acids in 20 g require for neutralization not more than 11.0ml of 0.1 N sodium hydroxide), heavy metals (0.001%), hy-droxyl value (between 154 and 162), iodine value (not morethan 5), and saponification value (between 176 and 182).

Ricinus Communis (Castor) Seed Oil is produced by coldpressing of the seeds of Ricinus communis and subsequent clar-ification of the oil by heat. Castor Oil does not contain ricinbecause ricin does not partition into the oil, due to its water-solubility. Hydrogenated Castor Oil is the end product of con-trolled hydrogenation of Ricinus Communis (Castor) Seed Oil.One of the simplest methods for obtaining Ricinoleic Acid isthe hydrolysis of castor oil.

Ricinus Communis (Castor) Seed Oil and Glyceryl Ri-cinoleate absorb UV light, with a maximum absorbance at270 nm.

Reportedly, Ricinus Communis (Castor) Seed Oil and Hy-drogenated Castor Oil were used in 769 and 202 cosmetic prod-ucts, respectively, in 2002. The following use frequencies werereported for Ricinoleic Acid and its salts and esters: GlycerylRicinoleate (16), Ricinoleic Acid (6), Sodium Ricinoleate (12),Zinc Ricinoleate (3), and Cetyl Ricinoleate (55).

The highest reported use concentration for Ricinus Commu-nis (Castor) Seed Oil is associated with lipsticks (81%). Othermaximum ingredient use concentrations are: Hydrogenated Cas-tor Oil (up to 39%), Glyceryl Ricinoleate (up to 12%), Zinc Ri-cinoleate (up to 2%), Cetyl Ricinoleate (up to 10%), and Octyl-dodecyl Ricinoleate (up to 5%).

Potassium Ricinoleate, Ethyl Ricinoleate, Glycol Rici-noleate, Isopropyl Ricinoleate, and Methyl Ricinoleate are notcurrently reported to FDA as in use, nor are there industry surveydata indicating a current use concentration.

Castor oil is classified by FDA as generally recognized assafe and effective for use as a stimulant laxative. An acceptabledaily intake (for man) of 0 to 0.7 mg/kg body weight has beenestablished by FAO/WHO for castor oil.

Castor oil is a triglyceride that is hydrolyzed in the small in-testine by pancreatic enzymes, leading to the release of glyceroland Ricinoleic Acid. Ricinoleic Acid was rapidly metabolizedin a study of adult rats fed a diet containing 48.4% castor oil for4 to 6 weeks. These animals did not have significant amountsof Ricinoleic Acid in phospholipids of the small intestine, liver,and skeletal muscle, nor in glycerides of the liver. A close cor-relation between the dose administered in the diet and the per-centage of Ricinoleic Acid in the feces (greater absorption of thesmaller dose) was noted in rats. Castor oil was readily absorbedand metabolized in two groups of male rats that were fed 10%castor oil in the diet (cholesterol-enriched and cholesterol-free,respectively) for 20 days. Fecal recovery of Ricinoleic Acid was



TABLE 6Case reports with patch test results for Castor Oil and Ricinoleic Acid esters and salts

Subjects Findings/patch test results References

22-year-old female(with cheilitis)

Cheilitis worsened after application of various lipsticks and lipcreams. Product concentrations of Castor Oil ranged from 10%to 67%. ++ patch test reactions to Castor Oil and each lipstickor lip cream that contained Castor Oil. Also, ++ patch testreactions to Ricinoleic Acid (as is), 30% Ricinoleic Acid inpetrolatum, and purified Castor Oil (as is). No reactions toproducts that did not contain Castor Oil.

Sai 1983

23-year-old female(history of facialeczema) with acutedermatitis of theface

++ reactions to Castor Oil and make-up remover containingCastor Oil.

Brandle et al. 1983

29-year-old female(history ofdeodorantdermatitis)

Acute edematous dermatitis on the lips and perioral area, whichspread to entire face and neck, after using a lipstick productcontaining Castor Oil. ++ patch test (Finn chambers,International Contact Dermatitis Research Group [ICDRG]recommendations) results for Castor Oil.

Andersen and Nielsen1984

24-year-old female Swelling of lips over 10-month period. Negative patch test resultsfor Castor Oil and five brands of lipstick containing Castor Oil.

Yoshikawa et al. 1986

31-year-old female(no history ofdermatitis)

Developed itchy rashes in the axillae, which spread over theentire body. Positive patch test reaction (++, at 38 and 96 h) toa deodorant that was used. Repeated open application testresults for Castor Oil and a Zinc Ricinoleate mixture (ZincRicinoleate (88%), triethanolamine, zinc resinate, isostearicacid, dipropylene glycol, sodium lactate, and abietic acid) werepositive.

Dooms-Goosens et al.1987

45-year-old female(history ofintolerance tocosmetics andadhesives)

Presented with an itchy dermatitis on both axillae, and redpapules scattered over face and trunk. Patch test resultsindicated a red erythematous response to a deodorant that wasused. Patch test results for Castor Oil were negative at 72 h and+/? at 96 h. Repeated open application test results for CastorOil were negative after 7 days; ++ patch test results for 20%Glyceryl Ricinoleate (in petrolatum) at 72 and 96 h. Also, ++reaction to Zinc Ricnoleate mixture (defined in preceding casereport) at 96 h. This mixture also produced an erythematous testresponse in 1 of 10 control subjects.

Dooms-Goosens et al.1987

40-year-old chemist(history of eczemadue to chemicalexposure on thejob)

Developed eczema on the knee 10 days after joint surgery.Positive patch test results for surgical adhesive containingCastor Oil. Negative patch test results for Castor Oil.

Jost et al. 1989

20-year-old female Allergic cheilitis (itching, swelling, and redness of the lips) afterusing a total of 16 lipstick products. Positive patch test resultsfor Castor Oil and each product.

Fisher 1991

17-year-old female(with lip dermatitis)

Positive patch test reactions to Castor Oil and 3 lipsticks. Fisher 1991


CASTOR OIL 69

TABLE 6Case reports with patch test results for Castor Oil and Ricinoleic Acid esters and salts (Continued)


17-year-old female(allergic to metals)

Developed itchy erythematovesicular reaction on right hand afterusing a liquid wart remover containing flexible collodion(contains 1.67% Castor Oil). + + + patch test reaction to wartremover. ++ patch test reactions to Castor Oil and 20% CastorOil in petrolatum. Negative patch test reactions to Castor Oil and20% Castor Oil in petrolatum in 15 control subjects.

Lodi et al. 1992

51-year-old female Developed two roundish, erythematous vesicular plaques in leftgluteal and right anterolateral neck regions (application sites)after 20 days of treatment with an anti-wart solution (flexiblecollodion, common component of wart removers, containsCastor Oil). ++ patch test reactions to Castor Oil 20% CastorOil in petrolatum, and the wart remover.

Tabar et al. 1993

65-year-old male(history of rashfollowing woodcutting in orchard)

Rash on face, neck, and hands. Same rash appeared 3 yearsearlier, following wood cutting. Patch test results for Castor Oil(100%) were negative.

Manzur et al. 1995

30-year-old female(history of mildatopic eczema)

Hand dermatitis after exposure to cream containing Castor Oiland zinc. + + + patch test reaction to Castor Oil. Negativeresults for 10 control subjects.

Wakelin et al. 1996

29-year-old female(nonatopic)

Sore, cracked lips, followed by vesicular facial edema, after use ofthe same lipstick product for several years. ++ patch test (Finnchambers, ICDRG criteria) results for Castor Oil.

Tan et al. 1997

24-year-old female(history of hayfever and dry lips)

Pruritic papules, swelling, and pigmentation on and around lipsafter applying lipstick. Negative patch test results for Castor Oil(as is).

Inoue et al. 1998

20-year-old armyrecruit

Rashes developed after applying a camouflage stick containing47.1% Castor Oil. A mildly pruritic vesicular eruption appearedon the neck, chin, face, and hands; swelling of eyelid alsoobserved. Symptoms lasted for 3 or 4 days.

Goon et al. 1999

43-year-old female(history of sinusaspergillosis andfacial edema afteroral dosing withtixocortol pivalate)

Recurrent facial dermatitis and cheilitis after use of a facialmoisturizer containing 8% Castor Oil. +/+ patch test (Finnchambers) reactions to the moisturizer, Castor Oil, 15% CastorOil in petrolatum, and 10% Castor Oil in petrolatum. + to ++reactions to several lipstick and lip balm products containingCastor Oil.

Le Coz and Ball 2000

51-year-old female Pruritic erythema in both axillae after use of a deodorantcontaining 76% Zinc Ricinoleate. One week later, developedacute contact dermatitis of the lips after using perfumed lipstickcontaining Glyceryl Ricinoleate. Lipstick was previouslytolerated. + patch test reaction to deodorant and lipstick. +patch test reaction to 30% Glyceryl Ricinoleate in petrolatum.Re-patch testing yielded the following results: 76% ZincRicinoleate in petrolatum (?+ reaction on day 3) and noreactions to 30%, 15%, or 1% Zinc Ricinoleate in petrolatum20% Glyceryl Ricinoleate in petrolatum (+ reaction on day 3),30% Glyceryl Ricinoleate in petrolatum (+ reaction on day 3),and Castor Oil, as is (no reaction).

Magerl et al. 2001




TABLE 6Case reports with patch test results for Castor Oil and Ricinoleic Acid esters and salts (Continued)


58-year-old female(history of allergyto adhesive tapes)

After knee surgery, acute contact dermatitis around surgicalincision rapidly became blistered and spread to right lower limb.Patch test results for Castor Oil (1% and 10% in petrolatum)were negative.

Reichert-Penetrat et al.2001

50-year-old female(history of allergyto adhesive tapes)

After hip surgery, acute dermatitis around surgical incision spreadto lower right limb. Patch test results for Castor Oil (1% and10% in petrolatum) were negative.

Reichert-Penetrat et al.2001

30-year-old female(with pigmentedcontact cheilitis)

Presented with scaly erythema with associated diffusehyperpigmentation and itchy swelling for past one year afterusing various lipsticks. ++ patch test reactions to RicinoleicAcid at day 3.

Leow et al. 2003

approximately 0.5% of the total ingested. 3,6-epoxyoctanedioicacid, 3,6-epoxydecanedioic acid, and 3,6-epoxydodecanedioicacid were excreted by rats given castor oil intragastrically. Theseacids were not detected in the urine prior to dosing with castoroil.

Following the oral administration of Hydrogenated CastorOil to rats at dietary concentrations of 0.865% and 8.65%, thedeposition of hydroxystearic acid in the abdominal fat and otherbody lipids was reported. In all cases, hydroxystearic acid wasaccompanied by hydroxypalmitic acid, hydroxymyristic acid,and hydroxylauric acid (hydroxystearic acid metabolites). Rici-noleic Acid or Methyl Ricinoleate administered by gastric intu-bation to male rats resulted in peak absorption of Ricinoleic Acidwithin 30 min post dosing in the following fractions: triglyceride,diglyceride, monoglyceride, and free fatty acid.

Castor oil (labeled with 131I) was administered to five hy-pertensive patients on the day before a scheduled intravenouspyelogram, with results demonstrating that castor oil can be ab-sorbed by human subjects, that absorption is inversely related tothe administered dose, and, at small doses (4 g), that absorptionis virtually complete.

Following oral administration of castor oil (10 to 15 ml) tothree healthy subjects, the following three epoxydicarboxylicacids were excreted in the urine: 3,6-epoxyoctanedioic acid;3,6-epoxydecanedioic acid; and 3,6-epoxydodecanedioic acid.

Castor oil caused a marked decrease in the transepidermalwater loss rate from full-thickness, cartilage-stripped skin fromthe ventral ear of the male Syrian golden hamster. In anotherstudy, Ricinoleic Acid enhanced the in vitro transdermal perme-ation of 5-fluorouracil in hairless mouse skin.

Oral dosing with Sodium Ricinoleate, Ricinoleic Acid, orcastor oil had both stimulatory and inhibitory effects on smoothmuscle (canine small bowel) contraction in vivo. Sodium Ri-cinoleate, but not Methyl Ricinoleate, depressed the smoothmuscle twitch response in a guinea pig ileum preparation atconcentrations ranging from 1.25 × 10−5 to 4 × 10−4 M.

Unlike prostaglandin E1 (chemically similar to RicinoleicAcid), Ricinoleic Acid did not induce dose-dependent stimula-tion of adenylate cyclase in villus cell (from hamster small in-testine) homogenates. Compared to saline-treated controls, cas-tor oil significantly reduced the infiltration of leukocytes andthe prostaglandin E2 (inflammatory mediator) content of the rataqueous humor and iris-ciliary body.

Sodium Ricinoleate significantly inhibited (considered mod-est; p < .05) cytokine-induced endothelial adhesion moleculeexpression when incubated with human saphenous vein endothe-lial cells. In a similar experiment, Ricinoleic Acid significantlydecreased IL-4-induced VACM-1 expression (50% inhibitoryconcentration between 10 and 100 µM). Neither cell numbernor viability was increased in this concentration range. Rici-noleic Acid did not inhibit TNFα-induced vascular cell adhesionmolecule-1 expression to any significant extent. Castor oil in thediet induced a significant increase in prostaglandin E2 concen-trations in tissues of the intestinal mucosa, placenta, amnion,and amniotic cells in groups of pregnant Wistar rats.

Castor oil did not have antimicrobial activity in the Staphylo-coccus aureus, Escherichia coli, or Candida albicans bacterialstrains. There was no correlation between Sodium Ricinoleateantibacterial activity against cells in suspension and antiplaqueactivity.

Following the oral administration of castor oil (2 ml), macro-scopic damage, characterized mainly by vasocongestion, wasobserved throughout the duodenum and jejunum in rats. Aftermale albino rats were dosed intraperitoneally with 100 mg Ri-cinoleic Acid, all animals were dead within 24 h. The acute oralLD50 for Ethyl Ricinoleate exceeded 5.0 g/kg in rats. A singleoral dose (2.5 ml/kg) of castor oil caused generalized hyper-emia of the intestinal mucosa up to 72 h post dosing in most of12 ponies. An acute oral LD50 of >10 g/kg was reported forHydrogenated Castor Oil in a study involving rats. The acutedermal LD50 for Ethyl Ricinoleate exceeded 5.0 g/kg in rabbits.One of the rabbits died. The skin reactions observed included


CASTOR OIL 71

moderate erythema in six rabbits, moderate edema in five rab-bits, and slight edema in one rabbit.

In an acute intravenous toxicity study in which eight mongreldogs were dosed with castor oil (single bolus dose = 0.1 ml/kg),none of the animals died. Erythema was the only clinical signthat was reported. An increase in blood histamine occurred inone animal.

The short-term subcutaneous administration of a vehicle con-sisting of castor oil and benzyl benzoate to groups of fiveC57Bl/6J mice caused morphological alterations suggestive ofstress-induced changes. Using electron microscopy, the changesobserved in the adrenal cortex included disruption of parenchy-mal mitochondria in the zona fasciculata, increase in the sizeof some of the mitochondria, loss of the vesicular orienta-tion of the inner mitochondrial membrane, and diminution ofthe mitochondrial matrix. Mitochondrial changes were also ob-served in the zona reticularis and zona fasiculata.

Intragastric administration of Ricinoleic Acid (single 0.1 mldose) to CD-1 specific pathogen–free mice resulted in the ero-sion of duodenal villi. In another study, perfusion of the rabbitcolon with Sodium Ricinoleate solution (5.0, 7.5, and 10 mM)led to mucosal damage (i.e., the loss of epithelial cells). A dose-response relationship for mucosal damage was noted.

In an NTP subchronic oral toxicity study, the administrationof diets containing up to 10% castor oil to groups of male and fe-male F344/N rats continuously for 13 weeks was not associatedwith any toxicities.

The subchronic oral toxicity of Hydrogenated Castor Oil (di-etary concentrations up to 17.3%) was evaluated in female ratsin a preliminary feeding trial. A reduced growth rate in rats fed8.65% and 17.3% Hydrogenated Castor Oil, respectively, wasthe only abnormality that was observed. Based on organ weightdeterminations and the results of hematological and microscopicexaminations, no adverse effects were observed.

In a 16-week study, groups of 15 male albino rats were feddiets containing 0.865% or 8.65% Hydrogenated Castor Oil. Ex-cept for the reduced growth rate in rats fed 8.65% HydrogenatedCastor Oil, no adverse effects were observed.

The instillation of undiluted castor oil (0.5 ml) into the rabbiteye resulted in an ocular injury score of 1 (maximum scorepossible = 20). In contrast, undiluted castor oil induced slightcongestion of the iris and conjunctiva in the rabbit eye in anotherstudy, but the instillation of castor oil (10 drops daily for 3 weeks)into the eyes of ten rabbits in a third study produced no damageto the corneal epithelium or endothelium.

Castor oil swabbed onto the dorsum of each of 216 albinoor Long-Evans rats daily for five days to 2 weeks produced amild effect on the epidermis. Undiluted castor oil was appliedfor 24 h to two areas on the dorsal surface of six albino angorarabbits. Severe skin irritation was observed. Undiluted castor oilapplied to the dorsal skin of six male Hartley guinea pigs, sixmale Wistar rats, and six miniature swine produced mild skinirritation in guinea pigs and rats, but not in miniature swine.Repeated applications of undiluted castor oil to the flanks of five

female albino rabbits daily for 30 days induced slight erythemaand edema. Both open skin irritation and repeated application (8weeks) tests for undiluted castor oil and 10% aqueous castor oilwere well tolerated by rabbits in another study. Slight reddeningof the application site (flank) was observed in a study in whichsix albino guinea pigs and six young pigs received applicationsof undiluted castor oil on 10 successive days.

In a predictive prick test in which seven normal subjectswere tested with an SLS extract of Castor Wax (concentra-tions up to 22,000 µg/ml), no immediate skin reactivity wasobserved. None of the seven subjects patch tested with theSLS Castor Wax extract or the remaining three extracts of Cas-tor Wax (concentrations not stated) had a delayed skin reac-tion. In a provocative prick test in the same study, three pa-tients with occupational hypersensitivity to castor allergens weretested with the SLS extract of Castor Wax at concentrations upto 22,000 µg/ml. All three patients had a positive reaction tothe SLS Castor Wax extract. None of the three patients patch-tested had a delayed reaction to the SLS Castor Wax extract orthe remaining three extracts of Castor Wax (concentrations notstated).

The positive skin reactions (immediate skin reactivity) in sen-sitized individuals, together with the positive PCA reactions inmice and positive direct RAST for reaginic castor allergens thatwere induced by SLS Castor Wax extract, indicate that allergensare present in Castor Wax at low concentrations.

Neither erythema nor edema was observed following a singletopical application of Ricinoleic Acid (in peanut oil) to the pawsof 8 to 10 male Swiss mice. The application of Ricinoleic Acid(in peanut oil) to the entire eyelid surface of each of six malealbino Dunkin-Hartley guinea pigs induced eyelid reddeningand edema at doses of 10, 30, or 100 mg. Cetyl Ricinoleatewas classified as a non-irritant following application to the skinof three male New Zealand albino rabbits. Diluted TEGODEOHY 77 (trade name mixture that generally contains >50% ZincRicinoleate) was applied, under occlusive patches and after patchremoval. Well-defined erythema was observed at 48 and 72 h atthe abraded sites of all six rabbits and at the intact sites of fourrabbits. This mixture did not produce skin sensitization in a studyinvolving 30 white guinea pigs.

Castor oil was not comedogenic when applied to the ears ofrabbits for 2 weeks, but there was a slight increase in keratincontent within the follicle, with essentially no change in thefollicular epithelium.

Sodium Ricinoleate caused dose-related increases in cyto-toxicity in cultures of epithelial cells that were isolated fromthe small intestines of male Syrian hamsters. In another study,Sodium Ricinoleate did not induce significant toxicity in hu-man saphenous vein endothelial cell cultures at concentrations≤25 µM. At concentrations of 0.1% and 1.0% Sodium Rici-noleate, applied to serosal surface or rat jejunum, a significantreduction in the number of ganglion cells in the myenteric orsubmucosal plexus was noted. This was not true for the lowesttest concentration (0.01%). Castor oil did not have a toxic effect



on the tubular epithelium following intraluminal injection intothe kidneys of five male white albino rats. In a study evaluat-ing the nephrotoxicity of cyclosporine, castor oil served as thevehicle control.

Neither castor oil nor Sodium Ricinoleate was mutagenicto the following Salmonella typhimurium strains either with orwithout metabolic activation: TA98, TA100, TA102, TA1535,and TA1537. Results were also negative for castor oil in Es-cherichia coli strain WP2/pKM102. Groups of male and femalemice that received diets containing 0.62%, 1.25%, 2.5%, 5.0%,and 10.0% castor oil (in DMSO) for 13 weeks had no evidenceof induction of micronuclei in peripheral erythrocytes. Castor oildid not induce sister chromatid exchanges either with or withoutmetabolic activation. Sodium Ricinoleate interfered with cell di-vision in an Escherichia coli strain, causing the organisms to de-velop as filaments. Ricinoleic Acid was inactive as a stimulatorof DNA synthesis and inducer of ornithine decarboxylase ac-tivity in the rat colon. Concentrations up to 10 mM resulted ininsignificant increases in [3H]dThd incorporation and did not in-crease the level of ornithine decarboxylase activity above controlvalues.

None of the 20 mice injected intravaginally with 2% Rici-noleic Acid (in gum tragacanth) had neoplasms or hyperplasticlesions of the corpus uteri, cervix uteri, vagina, or perineal skin.However, benign lung adenomas were observed in 10 of the13 mice dosed with Ricinoleic Acid and in 6 of the 24 vehiclecontrol mice that were killed after the 14th month of dosing.

Neither undiluted castor oil, Ricinoleic Acid, nor GlycerylRicinoleate was a tumor promoter in a study involving groupsof ten mice. However, the three test substances induced slightepidermal hyperplasia in groups of three mice following theapplication of each to a small area of skin in the interscapularregion.

Castor oil extract had a strong suppressive effect on S180 bodytumors in male Kunming mice. Its suppressive effect on ARSascites cancer was also very strong, with 64% of the ascitestumors in mice being completely cured. Compared to controls,the life extension rate was more than 136% (p < .0012).

Groups of mice and rats fed diets containing 0.62%, 1.25%,2.5%, 5.0%, and 10% Castor Oil continuously for 13 weekshad a slight decrease in epididymal weight (6% to 7%) in mid-and high-dose groups of male rats; however, this finding wasnot dose-related. No effects on any other male reproductive endpoint (testes weight and epididymal sperm motility, density, ortesticular spermatid head count) or female reproductive endpoint(estrous cycle length, or time spent in each phase of the cycle)were noted.

Female Wistar rats injected intramuscularly with castor oil(0.2 ml, single dose) on the first day after estrus had suppressedovarian folliculogenesis and anti-implantation and abortive ef-fects. Anticonceptive and estrogenic effects of a methanolextract of Ricinus communis var.minor seeds (ether-soluble frac-tion) were studied in adult albino Wistar rats, young albinoWistar rats, immature Swiss albino female mice, and adult fe-

male New Zealand white rabbits. Subcutaneous administrationof the extract produced anti-implantation, anticonceptive, andestrogenic activity in rats and mice.

Castor oil served as the vehicle control in a study evalu-ating the effect of long-term treatment with ICI 182,780 (anantiestrogen) on the rat testis. In the control group, four maleSprague-Dawley rats were injected subcutaneously with castoroil (0.2 ml) once per week and then killed 100 days after the firstinjection. Spermatogenesis appeared normal in each of the fourcontrol rats.

Castor oil (2 oz) was used to stimulate labor in 196 patients(between 37 and 42 weeks of gestation) with premature ruptureof membranes. The need for cesarean sections was nearly threetimes greater in the control group (15.7% incidence) than inpatients dosed with castor oil (5.6% incidence). No relationshipbetween dosing with Castor Oil (administered as a 60-ml dosein orange or apple juice), birth weight, and mode of delivery wasfound in a study in which castor oil was used to induce labor in52 pregnant women. The cesarean section rate for women dosedwith castor oil was 19.2% (10 of 52 women), compared to 8.3%(4 of 48 controls) in the untreated control group. No adverseoutcomes for the mother or fetus were identified.

Mild and transient discomfort and minor epithelial changeswere observed in the eyes of nine patients after treatment (in-stillation) with a castor oil solution four times daily for 15 days.In another study involving 100 patients, the instillation of castoroil affected the cornea and conjunctiva. Specifically, the degen-eration and death of epithelial cells and continuity breaks in theepithelium were observed.

Mild skin irritation was reported in 50 adult males patch testedwith undiluted castor oil (0.05 g applied to back). None of the1 to 20 patients, either suffering from or suspected of suffer-ing from contact allergy to cosmetic products, patch tested with30% Hydrogenated Castor Oil had irritant reactions. Undilutedcastor oil rubbed gently onto the right thigh of each of three malesubjects on 10 successive days produced, at microscopic exam-ination of excised skin, clear hyperchromasia and an increase inthe number of cells was observed in the basal cell layer. Slightwidening of the granular cell layer was also noted. No skin irri-tation was seen with 20% Ethyl Ricinoleate in petrolatum using32 healthy male volunteers in a 48-h closed patch test.

No skin sensitization or irritation was seen with 20% EthylRicinoleate in a maximization test using 32 healthy malevolunteers. In 49 patients with contact dermatitis patch-tested(48-h Finn chambers) with castor oil, none had a positivereaction. One of the 76 dermatitis patients patch-tested withCastor Oil had a positive reaction, observed only during thesecond reading (i.e., the day after the 30-min reading). Of 202consecutive patients with eczematous cheilitis who attendeda contact and occupational dermatoses clinic in Singapore,29 patients had positive reactions to Ricinoleic Acid. Of the29 positive reactions, 22 were considered relevant positives.In an allergenicity-photoallergenicity study, 103 patients sus-pected of having cosmetic-related dermatitis were patch tested


CASTOR OIL 73

with castor oil. One patient had a positive patch test reaction.None of the patients had a positive photopatch test reaction.

In case reports that included patch test results for castor oil,Ricinoleic Acid, or esters of Ricinoleic Acid, both positive andnegative reactions were reported. Of a group of 25 employees ata company involved with the preparation of plant products, 1 em-ployee had an allergic reaction to an extract of the castor oil bean.

DISCUSSIONThe CIR Expert Panel considered that the available data on

Ricinus Communis (Castor) Seed Oil, Hydrogenated Castor Oil,Ricinoleic Acid, and salts and esters of Ricinoleic Acid in thecurrent safety assessment are sufficient for evaluating the safetyof Glyceryl Ricinoleate and Glyceryl Ricinoleate SE, as well.Because Ricinus Communis (Castor) Seed Oil contains Rici-noleic Acid as the primary fatty acid group, safety test data onthe oil is considered broadly applicable to this entire group ofcosmetic ingredients. Overall, the available data demonstratefew toxic effects in acute, subchronic, or chronic toxicity tests.Additionally, there were no genotoxic effects of castor oil in invitro or in vivo tests. It was noted that the available data include a50-week chronic study in which none of the 20 mice injectedwith Ricinoleic Acid twice per week had neoplasms or hyper-plastic lesions of the corpus uteri, cervix uteri, vagina, or perinealskin. UV absorption spectra on Ricinus Communis (Castor) SeedOil and Glyceryl Ricinoleate indicate maximum absorbance at270 nm, suggesting that there would be no photosensitizationpotential of Glyceryl Ricinoleate or Ricinus Communis (Cas-tor) Seed Oil in human subjects at relevant solar UV exposures.

Reactions classified as either significantly irritating or al-lergic were not observed in a maximization test on Ethyl Ri-cinoleate involving 32 healthy male subjects. Although thereis a paucity of predictive patch test data on Ricinoleic Acidesters/salts, the Panel agreed that the negative guinea pig sen-sitization data on a trade name mixture containing more than50% Zinc Ricinoleate, in conjunction with the human predic-tive patch test data, may be extended to support the safety ofall of the cosmetic ingredients that are included in this safetyassessment.

The Panel did consider the 22 positive reactions to RicinoleicAcid in a retrospective study involving 202 consecutive patientswith eczematous cheilitis. Recognizing that this study representsa case series on cheilitis that involves a select patient popula-tion, the Panel agreed that the incidence of sensitization reac-tions reported in the study may be expected in that select patientgroup, but not in the general population. Based on the Panel’sexperience and expertise in the area of patient patch testing, theincidence of positive reactions to Ricinoleic Acid is generallyvery low.

In the absence of inhalation toxicity data on Ricinus Com-munis (Castor) Seed Oil, Hydrogenated Castor Oil, RicinoleicAcid, and salts and esters of Ricinoleic Acid in this safety assess-ment, the Panel determined that these ingredients can be used

safely in aerosolized products because packaging and use ensurethat particulates are not respirable (are greater than 10 µm). ThePanel reasoned that the particle size of anhydrous hair sprays (60to 80 µm) and pump hair sprays (>80 µm) is large comparedto the median aerodynamic diameter of 4.25 ± 1.5 µm for arespirable particulate mass.

The CIR Expert panel recognizes that certain ingredients inthis group are reportedly used in a given product category, butthe concentration of use is not available. For other ingredients inthis group, information regarding use concentration for specificproduct categories is provided, but the number of such productsis not known. In still other cases, an ingredient is not in currentuse, but may be used in the future.

Although there are gaps in knowledge about product use, theoverall information available on the types of products in whichthese ingredients are used and at what concentration indicatea pattern of use. Within this overall pattern of use, the ExpertPanel considers all ingredients in this group to be safe.

CONCLUSIONThe CIR Expert Panel concluded that Ricinus Communis

(Castor) Seed Oil, Hydrogenated Castor Oil, Glyceryl Rici-noleate, Glyceryl Ricinoleate SE, Ricinoleic Acid, PotassiumRicinoleate, Sodium Ricinoleate, Zinc Ricinoleate, Cetyl Rici-noleate, Ethyl Ricinoleate, Glycol Ricinoleate, Isopropyl Rici-noleate, Methyl Ricinoleate, and Octyldodecyl Ricinoleate aresafe as cosmetic ingredients in the practices of use and concen-trations as described in this safety assessment.

REFERENCESAchaya, K. T. 1971. Chemical derivatives of castor oil. J. Am. Oil Chem. Soc.

48:758–763.Allegri, R., G. C. Deschel, V. Filippi, M. Gibellini, E. Portioli, and D. Veneri.

1981. Proposal for the pharmacopoeia: hydrogenated castor oil [translation].Boll. Chim. Farm. 120:557–558.

Ames, B. N., J. McCann, and E. Yamasaki. 1975. Methods for detecting carcino-gens and mutagens with the Salmonella/mammalian-microsome mutagenicitytest. Mutat. Res. 31:347–364.

Andersen, K. E., and R. Nielsen. 1984. Lipstick dermatitis related to castor oil.Contact Dermatitis 11:253–254.

Aplin P.J., and Eiseo T. 1997. Ingestion of castor oil plant seeds. Med. J. Aust.167:260–261.

Ayorinde, F. O., K. Garvin, and K. Saeed. 2000. Determination of the fattyacid composition of saponified vegetable oils using matrix-assisted laser des-orption/ionization time-of-flight mass spectrometry. Rapid. Commun. MassSpectrom. 14:608–615.

Baynes, R. E., and J. E. Riviere. 2004. Mixture additives inhibit the dermalpermeation of the fatty acid, ricinoleic acid. Toxicol. Lett. 147:15–26.

Behrens-Baumann, W., S. Theuring, and H. Brewitt. 1986. The effect of topicalcyclosporin A on the rabbit cornea. A clinical and electron microscopic study.Graefes Arch. Clin. Exp. Ophthalmol. 224:520–552.

Binder, R. G., A. N. Booth, D. J. Robbins, and G. Fuller. 1970. Hydroxystearicacid deposition and metabolism in rats fed hydrogenated castor oil. Lipids5:832–837.

Blair, R. M., H. Fang, W. S. Branham et al. 2000. The estrogen receptor relativebinding affinities of 188 natural and xenochemicals: Structural diversity ofligands. Toxicol. Sci. 54:138–153.



Bower, D. 1999. Unpublished information on hair spray particle sizes providedat the September 9, 1999 CIR Expert Panel meeting.2

Boyland, D., F. J. C. Roe, and B. C. V. Mitchley. 1966. Test of certain constituentsof spermicide for carcinogenicity in genital tract of female mice. Br. J. Cancer20:184–189.

Brandle, I., A. Boujnah-Khouadja, and J. Foussereau. 1983. Allergy to castoroil. Contact Dermatitis 9:424–425.

Bronaugh, R. L., and R. F. Stewart. 1985. Methods for in vitro percutaneousabsorption studies. IV: The flow-through diffusion cell. J. Pharm. Sci. 74:64–66.

Beubler, E., and A. Schirgi-Degen. 1992. Stimulation of enterocyte protein ki-nase C by laxatives in vitro. J Pharm Pharmacol 45:59–62.

Budavari, S, ed. 1989. The Merck Index. An Encyclopedia of Chemicals, Drugs,and Biologicals, 11th ed., 290, 1307. Rahway, NJ: Merck & Co.

Bull, A. W., N. D. Nigro, W. A. Golembieski, J.D. Crissman, and L.J. Marnett.1984. In vivo stimulation of DNA snthesis and induction of ornithine decar-boxylase activity in rat colon by hydroperoxides, autoxidation products ofunsaturated fatty acids. Cancer Res 44:4924–4928.

Bull, A. W., N. D. Nigro, and L. J. Marnett. 1988. Structural requirements forstimulation of colonic cell proliferation by oxidized fatty acids. Cancer Res48:1771–1776.

Butcher, E. O. 1951. The effects of applications of various substances on theepidermis of the rat. J Invest Dermatol 16:85-90.

Butcher, E. O. 1952. The penetration of fat and fatty acid into the skin of the rat.J Invest Dermatol 21:43–48.

Campbell & Co. 2002. Castor oil & castor oil derivatives. Product data—castorwaxes. http://www.campbelluv.com/castor.html [accessed September 2004].

Capasso, F., N. Mascolo, G. Autore, and V. Romano. 1986. Laxatives andthe production of autacoids by rat colon. J Pharm Pharmacol 38:627–629.

Capasso, F., N. Mascolo, A. A. Izzo, and T. S. Gaginella. 1994. Dissociationof castor oil-induced diarrhea and intestinal mucosal injury in rat: Effect ofN G -nitro-l-arginine methyl ester. Br J Pharmacol 113:1127–1130.

Carpenter, C. P., and H. F. Smyth, Jr. 1946. Chemical burns of the rabbit cornea.Am J Ophthal 29:1363–1372.

Chakravarty, D., and A. Bose. 1963. A note on the preparation of ricinoleic acidby urea complexing. J Pharm Pharmacol 15:337–338.

Committee of Revision of the United States Pharmacopeial Convention. 2004a.The United States Pharmacopoeia, 27th ed., 348. Rockville, MD: UnitedStates Pharmacopeial Convention.

Committee of Revision of the United States Pharmacopeial Convention. 2004b.The National Formulary, 22nd ed., 2844. Rockville, MD: United States Phar-macopeial Convention.

Cornell University. 2001. Castor Oil. http://www.ansci.cornell.edu/plants/castorbean.html [accessed October 2003].

Cosmetic, Toiletry, and Fragrance Association (CTFA). 2004. Use concentrationdata from industry survey. Unpublished data submitted by CTFA, May 2004.3 pages.2

Croci T., M. Landi, X. Emonds-Alt, G. Le Fur, J. P. Maffrand, and L. Man-ara. 1997. Role of tachykinins in castor oil diarrhea in rats. Br J Pharmacol121:375–380.

Davis, L. 1984. The use of castor oil to stimulate labor in patients with prematurerupture of membranes. J Nurse Midwifery 29:366–370.

De Caterina, R., and W. Bernini. 1998. Structural requirements for inhibitionof cytokine-induced endothelial activation by unsaturated fatty acids. J LipidRes. 39:1062–1070.

De Caterina, R., H. Tanaka, T. Nakagawa, P. J. Hauptman, and P. Libby. 1995.The direct effect of injectable cyclosporine and its vehicle, cremophor, onendothelial vascular cell adhesion molecule-1 expression. Transplantation60:270–275.

2Available from the Director, Cosmetic Ingredient Review, 110117th Street, NW, Suite 412, Washington, DC 20036, USA.

De Groot, A. C., ed. 1994. Patch testing. Test concentrations and vehicles for3700 Chemicals, 2nd ed., 11, 145. Amsterdam: Elsevier.

Degussa. 2001. Product data record. TEGODEO HY 77. Unpublished data sub-mitted by CTFA, May 5, 2004. 2 pages.2

Dooms-Goossens, A. K. Dupre, A. Borghijs, C. Swinnen, M. Dooms, and H.Degreef. 1987. Zinc ricinoleate: Sensitizer in deodorants. Contact Dermatitis16:292–294.

Drugstore.com, Inc. 2004. Rite Aid Castor oil, stimulant laxative U.S.P. Packagedetails: Directions. http://www.drugstore.com [accessed December 2004].

Elder, R. L. ed. 1988. Final report on the safety assessment of glyceryl ricinoleate.J. Am. Coll. Toxicol. 7:721–739.

Fisher, A. A. 1991. Allergic cheilitis due to castor oil in lipsticks. Cutis 47:389–390.

Food and Drug Administration (FDA). 1985. Laxative drug products for over-the-counter human use; Tentative final monograph. Federal Register 50:2124–2158.

FDA. 1990. Wart remover drug products for over-the-counter human use. Finalmonograph. Federal Register 55:33246–33256.

FDA. 2002. Frequency of use of cosmetic ingredients.FDA database. Washing-ton, DC: FDA.

FDA. 2003a. OTC Drug Review Ingredient Report. FDA database. Washington,DC: FDA.

FDA. 2003b. Inactive Ingredients Guide (Redacted), January 1996.http://www.fda.gov/cder/drug/iig/default.htm [accessed August 2003].

Fox, D. A., M. L. Epstein, and P. Bass. 1983. Surfactants selectively ablateenteric neurons of the rat jejunum. J Pharmacol Exp Ther 227:538–544.

Frankel, E. N., W. E. Neff, D. D. Brooks, and K. Fujimoto. 1987. Fluorescenceformation from the interaction of DNA with lipid oxidation degradation prod-ucts. Biochim. Biophys. Acta 919:239–244.

Fredholt, K., D. H. Larsen, and C. Larsen. 2000. Modification of in vitro drugrelease rate from oily parenteral depots using a formulation approach [trans-lation]. Eur J Pharm Sci 11:231–237.

Fujimoto, M., N. Higashi, A. Kume, K. Ueda, and N. Hino. 1997. Patch testresults in 332 patients suspected of cosmetic dermatitis. Environ Dermatol4:268–276.

Fulton, J. E. Jr. 1989. Comedogenicity and irritancy of commonly used ingredi-ents in skin care products. J Soc Cosmet Chem 40:321–333.

Fulton, J. E. Jr., S. Bradley, A. Aqundez, and T. Black. 1976. Non–comedogeniccosmetics. Cutis 17:344–351.

Gaginella, T. S., and P. Bass. 1978. Laxatives: An update on mechanism ofaction. Life Sci. 23:1001–1010.

Gaginella, T. S., V.S. Chadwick, J. C. Debongnie, J. C. Lewis, and S. F. Phillips.1977a. Perfusion of rabbit colon with ricinoleic acid: Dose-related mucosalinjury, fluid secretion, and increased permeability. Gastroenterology 73:95–101.

Gaginella, T. S., A. C. Haddad, V. L. W. Go, and S. F. Phillips. 1977b. Cyto-toxicity of ricinoleic acid (castor oil) and other intestinal secretagogues onisolated intestinal epithelial cells. J Pharmacol Exp Ther 201:259–266.

Gaginella, T. S., S. F. Phillips, R. R. Dozois, and V. L. Go. 1978. Stimulation ofadenylate cyclase in homogenates of isolated intestinal epithelial cells fromhamsters. Effects of gastrointestinal hormones, prostaglandins, and deoxy-cholic and ricinoleic acids. Gastroenterology 74:11–15.

Gao, J., N.-.H. Sun, F.-Y. Wang, and N. Hao. 1999. Effects of castor oil-diet onthe synthesis of prostaglandin E2 in pregnant rats [translation]. Zhonghua FuChan Ke Za Zhi 34:147–149.

Garry, D., R. Figueroa, J. Guillaume, and V. Cucco. 2000. Use of castor oil inpregnancies at term. Altern Ther Health Med. 6:77–79.

Gennaro, A. R., ed. 1990. Remington’s Pharmaceutical Sciences, 18th ed., 785.Easton, PA: Mack Publishing.

Gluud, B. S., T. Boesen, and M. Norn. 1981. The effect of a fatty vehicle on thecornea and conjunctiva. In vivo staining following instilling of oil [transla-tion]. Ugeskr Laeger 143:2345–2347.

Gohte, C. J., G. Wieslander, K. Ancker, and M. Forsbeck. 1983. Buckwheatallergy: Health food, an inhalation health risk. Allergy 38:155–159.


CASTOR OIL 75

Goon, A. T.-J., P. P.-L. Ng, and S.-K. Ng. 1999. Allergic contact dermatitis frommilitary camouflage. Contact Dermatitis 40:290–291.

Gottschalck, T. E., and G. N. McEwen, Jr., eds. 2004. International CosmeticIngredient Dictionary and Handbook, 10th ed. Washington, DC: CTFA.

Grainger, D. N., R. Cross, and J. A. Barrowman. 1982. Effects of various sec-retagogues and human carcinoid serum on lymph flow in the cat ileum. Gas-troenterology 83:896–901.

Grant J, ed. 1972. Hackh’s Chemical Dictionary, 4th ed., 584. New York:McGraw-Hill Book Co.

Guillot, J. P., J. Y. Giauffret, and M. C. Martini. 1979. Etude de tolerancesoculaire et cutanee chez la lapin, de differentes matieres premieres utiliseesen cosmetologie, et provenant de fabrications diverses (2eme partie). Int. J.Cosmet. Sci. 1:27–57.

Gunstone, F. D. 1989. Chemical reactions of fats and oils. Biochem Soc Trans17:1141–1142.

Hachiya, N. 1987. Evaluation of chemical genotoxicity by a series of short-termtests. Akita J Med 14:269–292.

Hagenfeldt, L., L. Blomquist, and T. Midtvedt. 1986. Epoxydicarboxylicaciduria resulting from the ingestion of castor oil. Clin Chim Acta 161:157–163.

Hashimoto, Y., T. Sugai, A. Shoji, S. Asoh, K. Watanabe, and A. Inoue. 1990.Incidence of positive reactions in patch tests with ingredients of cosmeticproducts in 1989 and representative cases of cosmetic dermatitis (Translation).Skin Res. 32:115–124.

Haworth, S., T. Lawlor, K. Mortelmans, W. Speck, and E. Zeiger. 1983.Salmonella mutagenicity test results for 250 chemicals. Environ Mutagen5:3–142.

Hino, N., M. Ikushima-Fujimoto, K. Ueda, A. Kume, and N. Higashi. 2000.Patch test results in 346 patients of suspected cosmetic dermatitis (1993–1996) [translation]. Environ Dermatol 7:144–153.

Hui, Y. H., ed. 1996. Bailey’s Industrial Oil & Fat Products. Industrial andConsumer Nonedible Products from Oils and Fats, 5th ed., vol. 5., 368. NewYork: John Wiley & Sons.

Ihara-Watanabe, M., T. Shiroyama, G. Konda, H. Umekawa, T. Takahashi, T.Yamada and Y. Furuichi. 1999. Effects of castor oil on lipid metabolism inrats. Biosci Biotechnol Biochem 63:595–597.

Inoue, A, A. Shoji, and S. Aso. 1998. Allergic lipstick cheilitis due to ester gumand ricinoleic acid. Contact Dermatitis 39:39.

International Bio-Research, Inc. 1977a. Delayed contact sensitization (guineapigs). Compound: “Grillocin HY 77” (undiluted) (Translation). Unpublisheddata submitted by CTFA. 18 pages.2

International Bio-Research, Inc. 1977b. Patch test for primary skin irritationand corrosivity of the compound: “Grillocin HY 77” (10% soy bean oil).Unpublished data submitted by CTFA. 7 pages.2

Jensen, P. A., and D. Obrien. 1993. Industrial hygiene. In: Aerosol Measurement.Principles, Techniques and Applications, ed. K. Willeke and P.A. Baron, 538–540. New York: John Wiley and Sons.

Johnsen, M. A. 2004. The influence of particle size. Spray Technology andMarketing. November:24–27.

Johnson, C. M., J. M. Cullen, and M. C. Roberts. 1993. Morphologic character-ization of castor oil-induced colitis in ponies. Vet Pathol 30:248–255.

Jost, T., Y. Sell, and J. Foussereau. 1989. Contact allergy to Manilla resin.Nomenclature and physico-chemistry of Manilla, kauri, damar and copalresins. Contact Dermatitis 21:228–238.

Kathren, R. L., H. Price, J. C. Rogers. 1959. Air-borne castor-bean pomaceallergy; a new solution to an old problem. AMA Arch Ind Health 19:487–489.

Kato, A., and Y. Yamaura.1970. A rapid gas chromatographic method for thedetermination of fatty acid compositions of soybean oil and castor oil. ChemInd 39:1260.

KIC Chemicals, Inc. 2004. Hydrogenated castor oil, standard grade. Specifica-tions. http://www.kicchem.com/hcostandard.htm [accessed September 2004].

Laboratoire De Recherche Et D’Experimentation. 1994. Acute oral toxicity andskin irritation and/or corrosion tests on cetyl ricinoleate. Unpublished datasubmitted by CTFA, April 13, 2004. 2 pages.2

Langer, K. H., W. Thoenes, and M. Wiederholt.1968. Light and electronmicroscopic investigations of proximal convoluted tubules of the rat kid-ney after intraluminal injection of oil [translation]. Pflugers Arch 302:149–165.

Larsen, S. W., E. Rinvar, O. Svendsen, J. Lykkesfeldt, G. J. Friis, and C. Larsen.2001. Determination of the disappearance rate of iodine-125 labelled oilsfrom the injection site after intramuscular and subcutaneous administrationto pigs. Int J Pharm 230:67–75.

le Coz, C. J., and C. Ball. 2000. Recurrent allergic contact dermatitis and cheilitisdue to castor oil. Contact Dermatitis 42:114–115.

Lehrer, S. B, R. M. Karr, D. J. G. Muller, and J.E. Salvaggio. 1980. Detectionof castor allergens in castor wax. Clin. Allergy 10:33–41.

Leow, Y. H., S. H. Tan, and S. K. Ng. 2003. Pigmented contact cheilitis fromricinoleic acid in lipsticks. Contact Dermatitis 49:48–49.

Lewis, R. J. Sr. 1997. Hawley’s Condensed Chemical Dictionary, 13th ed., 221,749, 922, 972, 1027, 1200. New York: John Wiley & Sons.

Lewis, R. J., Sr., ed. 2000. Sax’s Dangerous Properties of Industrial Materi-als,10th ed., 738. New York: John Wiley & Sons.

Lide, D. R., and H. P. R. Frederiske, eds. 1993. CRC Handbook of Chemistryand Physics, 74th ed., 3-453. Boca Raton, FL: CRC Press.

Lieb, L. M., R. A. Nash, J. R. Matias, and N. Orentreich. 1988. A new in vitromethod for transepidermal water loss: A possible method for moisturizerevaluation. J Soc Cosmet Chem 39:107–119.

Lim, S. W., and C. L. Goh. 2000. Epidemiology of eczematous cheilitis ata tertiary dermatological referral centre in Singapore. Contact Dermatitis43:322–326.

Litvinova, L. B., and T. V. Fedorchenko. 1994. The effect of plant oils on thefemale reproductive system [translation]. Eksp Klin Farmakol 57:49–51.

Lodge, N. J. 1994. Direct vasoconstrictor effects of sandimmune (cyclosporineA) are mediated by its vehicle Cremophor EL: Inhibition by the thromboxaneA2/prostaglandin endoperoxide receptor antagonist ifetroban. J PharmacolExp Ther 271:730–734.

Lodi, A., S. Leuchi, L. Mancini, G. Chiarelli, and C. Crosti. 1992. Allergyto castor oil and colophony in a wart remover. Contact Dermatitis 26:266–267.

Lorenz, W., A. Schmal, H. Schult et al. 1982. Histamine release and hypotensivereactions in dogs by solubilizing agents and fatty acids: Analysis of variouscomponents in cremophor El and development of a compound with reducedtoxicity. Agents Actions 12:64–80.

Magerl, A., R. Heiss, and P. J. Frosch. 2001. Allergic contact dermatitis fromzinc ricinoleate in a deodorant and glyceryl ricinoleate in a lipstick. ContactDermatitis 44:119–121.

Maier, M., D. Staupendahl, H. R. Duerr, and H. J. Refior. 1999. Castor oildecreases pain during extracorporeal shock wave application. Arch OrthopTrauma Surg 119:423–427.

Manzur, F., F. El Sayed, and J. Bazex. 1995. Contact allergy to cinnamic aldehydeand cinnamic alcohol in Oleophytal. Contact Dermatitis 32:55.

Masri, M. S., L. A. Goldblatt, F. DeEds, and G. O. Kohler. 1962. Relation ofcathartic activity to structural modifications of ricinoleic acid of castor oil. JPharm Sci 51:999–1002.

Mathias, J. R., J. L. Martin, T. W. Burns, G. M. Carlson, and R. P. Shields. 1978.Ricinoleic acid effect on the electrical activity of the small intestine in rabbits.J Clin Invest 61:640–644.

McKeon, T. A., G. Q. Chen, and J. T. Lin. 2000. Biochemical aspects of castoroil biosynthesis. Biochem Soc Trans 28:972–974.

Meyer, F. U., C. Wollmann, N. Exner, and G. Exner. 1976. Comparative studieson the skin of guinea pigs, swine and man following the effect of variousexternal agents [translation]. Dermatol Monatsschr 162:986–991.

Migally, N. 1979. Effect of castor oil and benzyl benzoate used as a vehicle forantiandrogens on the adrenal cortex. Arch Androl 2:365–369.

Mitri, F., G. J. Hofmeyr, and C. J. Van Geldren. 1987. Meconium during labor–self-medication and other associations. SAMJ 431–433.

Mordenti, J. J., R. E. Lindstrom, and J. M. Tanzer. 1982. Activity of sodiumricinoleate against in vitro plaque. Pharm Sci 71:1419–1421.



Morehouse, J. L., R. D. Specian, J. J. Stewart, and R. D. Berg. 1986. Translo-cation of indigenous bacteria from the gastrointestinal tract of mice after oralricinoleic acid treatment. Gastroenterology 91:673–682.

Morris, J. A., A. Khettry, and E. W. Seitz. 1979. Antimicrobial activityof aroma chemicals and essential oils. J. Am. Oil Chem. Soc. 56:595–603.

Morris, W. E., and S. C. Kwan. 1983. Use of the rabbit ear model in evaluating thecomedogenic potential of cosmetic ingredients. J Soc Cosmet Chem 34:215–225.

Motoyoshi, K., Y. Toyoshima, M. Sato, and M. Yoshimura. 1979. Compar-ative studies on the irritancy of oils and synthetic perfumes to the skinof rabbit, guinea pig, rat, miniature swine and man. Cosmet Toilet 94:41.

Muldoon, D. F., E. A. Hassoun, and S. J. Stohs. 1992. Ricin-induced hepaticlipid peroxidation, glutathione depletion, and DNA single-strand breaks inmice. Toxicon 30:977–984.

National Academy of Sciences (NAS). 1996. Food Chemicals Codex, 4th ed.,94 Washington, DC: National Academy Press.

National Toxicology Program (NTP). 1992. NTP technical report on the toxicitystudies of castor oil (CAS No. 8001-79-4) in F344/N rats and B6C3F1 mice(dosed feed studies). NTIS Report No. PB93151439.

NTP. 2003. NTP Chemical Repository. Castor Oil. Research Triangle Park, NC:NTP.

Nikitakis, J. M., and G. N. McEwen Jr., eds. 1990. CTFA Compendium ofCosmetic Ingredient Composition—Descriptions I and II. Washington, DC:CTFA.

Ohia, E. O., M. Mancino, and P. S. Kulkarni. 1992. Effects of steroids andimmunosuppressive drugs on endotoxin-uveitis in rabbits. J Ocul Pharmacol8:295–307.

Okui, S., M. Uchiyama, R. Sato, and M. Mizugaki. 1964. Metabolism of hydroxyfatty acids. III. Characterization of hydroxy acids in depot fat after feeding ofricinoleic acid. J Biochem 55:81–86.

Okwuasaba, F. K., U. A. Osunkwo, M. M. Ekwenchi, et al. 1991. Anticonceptiveand estrogenic effects of a seed extract of Ricinus communis var. minor. JEthnopharmacol 34:141–145.

Oliveira, C. A., K. Carnes, L. R. Franca, and R. A. Hess. 2001. Infertility and tes-ticular atrophy in the antiestrogen-treated adult male rat. Biol Reprod 65:913–920.

Ordman, D. 1955. An outbreak of bronchial asthma in South Africa, affectingmore than 200 persons, caused by castor bean dust from an oil-processingfactory. Int Arch Allergy 7:10.

Paul, H., and C. M. McCay. 1942. The utilization of rats by herbivora. ArchBiochem 1:247–253.

Paulus, G. L., and M. H. Champion. 1972. Gas-liquid chromatographic deter-mination of castor oil as methyl ricinoleate in lipstick. J Soc Cosmet Chem23:313–319.

Physical & Theoretical Chemistry Lab. 2004. Safety (MSDS) data for hy-drogenated castor oil. http://ptcl.chem.ox.ac.uk/MSDS/HY/hydrogenatedcastor oil.html [accessed September 2004].

Pinto, A., A. Calignano, N. Mascolo, G. Autore, and F. Capasso. 1989. Castoroil increases intestinal formation of platelet-activating factor and acid phos-phatase release in the rat. Br J Pharmacol 96:872–874.

Poch, G. 1971. Assay of phosphodiesterase with radioactively labeled cyclic3′5′-AMP as substrate. Naunyn-Schmiedeberg’s Arch Pharmacol 268:272–299.

Polgar, P., and L. Taylor. 1977. Effects of prostaglandin on substrate uptake andcell division in human diploid fibroblasts. Biochem J. 162:1–8.

Racusen, L. C., B. C. Kone, A. Whelton, and K. Solez.1986. Renal bloodflow, glomerular filtration rate, and renal morphology in cyclosporine-induced acute renal failure in Munich-Wistar rats. Am J Kidney Dis 8:319–322.

Ramsey, J. D., T. D. Lee, M. D. Osselton, and A. C. Moffat. 1980. Gas liquidchromatographic retention indices of 296 nondrug substances on SE-30 or OV-1 likely to be encountered in toxicological analyses. J Chromatogr 184:185–206.

Rantuccio, F., D. Sinisi, A. Scardigno, and C. Coviello. 1981. Histologicalchanges in rabbits after application of medicaments and cosmetic bases. II.Contact Dermatitis 7:94–97.

Rao, M. K., N. Risser, and E. G. Perkins. 1969. The incorporation of ricinoleicacid into rat lymph lipids. Proc Soc Exp Biol Med 131:1369–1372.

Ratner, B., and H. L. Gruehl. 1929. Respiratory anaphylaxis (asthma) and ricinpoisoning induced with castor bean dust. Am J Hyg 10:236.

Reichert-Penetrat, S., A. Barbaud, E. Reichert-Penetrat, F. Granel, and J.-L.Schmutz. 2001. Allergic contact dermatitis from surgical paints. Contact Der-matitis 45:116–117.

Research Institute for Fragrance Materials (RIFM). 2000. Fragrance raw mate-rials monographs. Ethyl ricinoleate. FCT 38:S91–S92.

Sai, S. 1983. Lipstick dermatitis caused by castor oil. Contact Dermatitis 9:75,524.

Salomon, Y., C. Londos, and M. Rodbell. 1974. A highly sensitive adenylatecyclase assay. Anal Biochem 58:541–548.

Sasol North America, Inc. No date. UV spectrum for castor oil and glycerylricinoleate. Unpublished data submitted by CTFA, April 14, 2004. 1 page.2

Scarpa, A., and A. Guerci.1982. Various uses of the castor oil plant (Ricinuscommunis L.). A review. J Ethnopharmacol 5:117–137.

Secchi, A. G., M. S. Tognon, and A. Leonardi.1990. Topical use of cyclosporinein the treatment of vernal keratoconjunctivitis. Am J Ophthalmol 110:641–645.

Shubik, P. 1950. Studies on the promoting phase in the stages of carcinogenesisin mice, rats, rabbits, and guinea pigs. Cancer Res 10:13–17.

Simon, B., and H. Kather. 1980. Interaction of laxatives with enzymes of cyclicAMP metabolism from human colonic mucosa. Eur J Clin Invest 10:231–234.

Smolinske, S. C. 1992. Handbook of Food, Drug, and Cosmetic Excipients, 70.Boca Raton, FL: CRC Press.

Song, J. F., C. A. Lau-Cm, and K. H. Kim. 2001. Monohydroxylation andesterification as determinants of the effects of cis- and trans-9-octadecenoicacids on the permeation of hydrocortisone and 5-fluorouraci across hairlessmouse skin in vitro. Int J Pharmaceut 212:153–160.

Srinivasulu, C., and S.N. Mahapatra. 1973. A rapid method for detecting ground-nut oil in castor oil. J Chromatogr 86:261–262.

Steingrub, J. S., T. Lopez, D. Teres, and R. Steingart. 1988. Amniotic fluidembolism associated with castor oil ingestion. Crit Care Med 16:642–643.

Stewart, J. J., and P. Bass. 1976. Effects of ricinoleic acid and oleic acids on thedigestive contractile activity of the canine small and large bowel. Gastroen-terology 70:371–376.

Stewart, J. J, T. S. Gaginella, and P. Bass. 1975. Actions of ricinoleic acid andstructurally related fatty acids on the gastrointestinal tract. I. Effects on smoothmuscle contractility in vitro. J Pharmacol Exp Ther 195:347–354.

Stewart, W. C., and R. G. Sinclair. 1945. The absence of ricinoleic acid fromphospholipids of rats fed castor oil. Arch Biochem 8:7.

Stubiger, G., E. Pittenauer, and G. Allmaier. 2003. Characterization of castoroil by on-line and of-line non-aqueous reverse-phase high-performance liq-uid chromatography-mass spectrometry (APCI and UV/MALDI). PhytochemAnal 14:337–346.

Tabar, A. I., M. D. Muro, S. Quirce, and J. M. Olaguibel. 1993. Contact dermatitisdue to sensitization to lactic acid and castor oil in a wart remover solution.Contact Dermatitis 29:49–50.

Tan, B. B., A. L. Noble, M. E. Roberts, J. T. Lear, and J. S. English. 1997.Allergic contact dermatitis from oleyl alcohol in lipstick cross-reacting withricinoleic acid in castor oil and lanolin. Contact Dermatitis 37:41–42.

Thompson, W. G. 1980. Laxatives: Clinical pharmacology and rational use.Drugs 19:49–58.

TNO BIBRA International Ltd. 1999. Toxicity profile. Castor oil. Surrey, UnitedKingdom: TNO BIBRA International Ltd. 9 pages.

Uchiyama, M., R. Sato, and M. Mizugaki. 1963. Characterization of hydrox-yacids in depot fat after feeding of ricinoleic acid. Biochem Biophys Acta70:344–346.

Vanderhoek, J. Y., R. W. Bryant, and J. M. Bailey. 1980. Communication. 15-hydroxy-5,8,11,13-eicosatetraenoic acid. A potent and selective inhibitor ofplatelet lipoxygenase. J Biol Chem 255:5996–5998.


CASTOR OIL 77

Vieira, C, S. Evangelista, R. Cirillo, R. Terracciano, A. Lippi, C.A. Maggi, andS. Manzini. 2000. Antinociceptive activity of ricinoleic acid, a capsaicin-like compound devoid of pungent properties. Eur J Pharmacol 407:109–116.

Vieira, C., S. Tetzer, S. K. Sauer, et al. 2001. Pro- and anti-inflammatory ac-tions of ricinoleic acid: Similarities and differences with capsaicin. Naunyn-Schmiedeberg’s Arch Pharmacol 364:87–95.

Wakelin, S. H., A. J. Harris, and S. Shaw. 1996. Contact dermatitis from castoroil in zinc and castor oil cream. Contact Dermatitis 35:259.

Watson, W. C., and R. S. Gordon Jr. 1962. Studies on the digestion, absorptionand metabolism of castor oil. Biochem Pharmacol 11:229–236.

Watson, W. C., R. S. Gordon Jr, A. Karmen, and A. Jover. 1963. The absorptionand excretion of castor oil in man. J Pharm Pharmacol 15:183–188.

Whiteside-Carlson, V., B. F. Feaster, and W. W. Carlson. 1955. Filament induc-tion in Escherichia coli by ricinoleic acid. Proc Soc Exp Biol Med 89:382–385.

Wineburg, J. P., and D. Swern. 1973. NMR chemical shift reagents in struc-tural determination of lipid derivatives: III. Methyl ricinoleate and methyl12-hydroxystearate. J Am Oil Chem Soc 50:142–146.

World Health Organization (WHO) .1980. Evaluation of certain food additives.Twenty-third report of the Joint FAO/WHO Expert Committee on Food Addi-tives, 1–45. World Health Organization Technical Report Series 648. Geneva:WHO.

Xie, S. A., D. S. Liu, B. L. Li, Z. H. Wang, and J.Y. Tao. 1992. Antitumor effectof castor oil extract [translation]. Zhongguo Zhong Yao Za Zhi 17:560–561.

Yagaloff, K. A., L. Franco, F. Simko, and B. Burghardt. 1995. Essentialfatty acids are antagonists of the leukotriene B4 receptor. ProstaglandinsLeukotriene Essent. Fatty Acids 52:293–297.

Yahagi, T., M. Degawa, Y. Seino, T. Matsushima, M. Nagao, T. Sugimura, and Y.Hashimoto. 1975. Mutagenicity of carcinogenic azo dyes and their derivatives.Cancer Lett 1:91–96.

Yoshikawa, K., T. Kozuka, T. Doi, Y. Kataoka, K. Fujimoto, and S. Hashimoto.1986. A case of allergic contact dermatitis to castor oil. 10th AnniversaryMeeting of Japan Patch Test Research Group on Contact Dermatitis and PatchTest VII, Kobe, Japan, December 7–8, 1985. Skin Res 28(Suppl. 2):263–265.

Zeiger, E., B. Anderson, S. Haworth, T. Lawlor, and K. Mortelmans. 1988.Mutagenicity tests: IV. Results from the testing of 300 chemicals. EnvironMol Mutagen 11(Suppl. 12):1–158.


GLYCERYL BEHENATE 03A - Eyebrow Pencil 2GLYCERYL BEHENATE 03B - Eyeliner 1GLYCERYL BEHENATE 03C - Eye Shadow 2GLYCERYL BEHENATE 03D - Eye Lotion 1GLYCERYL BEHENATE 03F - Mascara 12GLYCERYL BEHENATE 03G - Other Eye Makeup Preparati 2GLYCERYL BEHENATE 05C - Hair Straighteners 1GLYCERYL BEHENATE 05G - Tonics, Dressings, and Othe 2GLYCERYL BEHENATE 07C - Foundations 4GLYCERYL BEHENATE 07E - Lipstick 7GLYCERYL BEHENATE 07I - Other Makeup Preparations 3GLYCERYL BEHENATE 08B - Cuticle Softeners 1GLYCERYL BEHENATE 08G - Other Manicuring Preparation 1GLYCERYL BEHENATE 10E - Other Personal Cleanliness P 1GLYCERYL BEHENATE 12A - Cleansing 6GLYCERYL BEHENATE 12C - Face and Neck (exc shave) 7GLYCERYL BEHENATE 12D - Body and Hand (exc shave) 6GLYCERYL BEHENATE 12F - Moisturizing 17GLYCERYL BEHENATE 12G - Night 2GLYCERYL BEHENATE 12H - Paste Masks (mud packs) 1GLYCERYL BEHENATE 12J - Other Skin Care Preps 10GLYCERYL BEHENATE 13B - Indoor Tanning Preparations 1

GLYCERYL CAPRATE 01B - Baby Lotions, Oils, Powders, 1GLYCERYL CAPRATE 03B - Eyeliner 1GLYCERYL CAPRATE 03C - Eye Shadow 1GLYCERYL CAPRATE 03D - Eye Lotion 2GLYCERYL CAPRATE 07A - Blushers (all types) 2GLYCERYL CAPRATE 07B - Face Powders 1GLYCERYL CAPRATE 07C - Foundations 1GLYCERYL CAPRATE 07E - Lipstick 7GLYCERYL CAPRATE 07I - Other Makeup Preparations 1GLYCERYL CAPRATE 10B - Deodorants (underarm) 5GLYCERYL CAPRATE 11A - Aftershave Lotion 3GLYCERYL CAPRATE 11E - Shaving Cream 3GLYCERYL CAPRATE 11G - Other Shaving Preparation P 1GLYCERYL CAPRATE 12A - Cleansing 5GLYCERYL CAPRATE 12C - Face and Neck (exc shave) 6GLYCERYL CAPRATE 12D - Body and Hand (exc shave) 2GLYCERYL CAPRATE 12F - Moisturizing 2GLYCERYL CAPRATE 12G - Night 1GLYCERYL CAPRATE 12H - Paste Masks (mud packs) 2GLYCERYL CAPRATE 12I - Skin Fresheners 4GLYCERYL CAPRATE 12J - Other Skin Care Preps 6

GLYCERYL CAPRYLATE 03B - Eyeliner 9GLYCERYL CAPRYLATE 03C - Eye Shadow 7GLYCERYL CAPRYLATE 03D - Eye Lotion 6GLYCERYL CAPRYLATE 03F - Mascara 3GLYCERYL CAPRYLATE 03G - Other Eye Makeup Preparati 4GLYCERYL CAPRYLATE 05A - Hair Conditioner 3GLYCERYL CAPRYLATE 05F - Shampoos (non-coloring) 1GLYCERYL CAPRYLATE 05G - Tonics, Dressings, and Othe 2GLYCERYL CAPRYLATE 07A - Blushers (all types) 11GLYCERYL CAPRYLATE 07B - Face Powders 16GLYCERYL CAPRYLATE 07C - Foundations 7GLYCERYL CAPRYLATE 07E - Lipstick 20


GLYCERYL CAPRYLATE 07F - Makeup Bases 2GLYCERYL CAPRYLATE 07H - Makeup Fixatives 1GLYCERYL CAPRYLATE 07I - Other Makeup Preparations 10GLYCERYL CAPRYLATE 10B - Deodorants (underarm) 2GLYCERYL CAPRYLATE 11D - Preshave Lotions (all types) 1GLYCERYL CAPRYLATE 12A - Cleansing 5GLYCERYL CAPRYLATE 12C - Face and Neck (exc shave) 25GLYCERYL CAPRYLATE 12D - Body and Hand (exc shave) 12GLYCERYL CAPRYLATE 12F - Moisturizing 19GLYCERYL CAPRYLATE 12G - Night 6GLYCERYL CAPRYLATE 12H - Paste Masks (mud packs) 4GLYCERYL CAPRYLATE 12I - Skin Fresheners 6GLYCERYL CAPRYLATE 12J - Other Skin Care Preps 8

GLYCERYL CAPRYLATE/CAPRATE 05B - Hair Spray (aerosol fixatives) 1GLYCERYL CAPRYLATE/CAPRATE 05F - Shampoos (non-coloring) 1

GLYCERYL COCOATE 05F - Shampoos (non-coloring) 2GLYCERYL COCOATE 05I - Other Hair Preparations 1GLYCERYL COCOATE 12C - Face and Neck (exc shave) 5GLYCERYL COCOATE 12D - Body and Hand (exc shave) 5GLYCERYL COCOATE 12H - Paste Masks (mud packs) 1

GLYCERYL ETHYLHEXANOATE/STEARATE/ADIPATE 03B - Eyeliner 1GLYCERYL ETHYLHEXANOATE/STEARATE/ADIPATE 03C - Eye Shadow 20GLYCERYL ETHYLHEXANOATE/STEARATE/ADIPATE 05G - Tonics, Dressings, and Othe 1GLYCERYL ETHYLHEXANOATE/STEARATE/ADIPATE 07A - Blushers (all types) 6GLYCERYL ETHYLHEXANOATE/STEARATE/ADIPATE 07B - Face Powders 4GLYCERYL ETHYLHEXANOATE/STEARATE/ADIPATE 07C - Foundations 4GLYCERYL ETHYLHEXANOATE/STEARATE/ADIPATE 07E - Lipstick 1GLYCERYL ETHYLHEXANOATE/STEARATE/ADIPATE 07F - Makeup Bases 1GLYCERYL ETHYLHEXANOATE/STEARATE/ADIPATE 12A - Cleansing 1

GLYCERYL HYDROGENATED ROSINATE 03C - Eye Shadow 1GLYCERYL HYDROGENATED ROSINATE 03F - Mascara 13GLYCERYL HYDROGENATED ROSINATE 05G - Tonics, Dressings, and Othe 1GLYCERYL HYDROGENATED ROSINATE 07E - Lipstick 6GLYCERYL HYDROGENATED ROSINATE 12B - Depilatories 7GLYCERYL HYDROGENATED ROSINATE 12J - Other Skin Care Preps 1

GLYCERYL HYDROXYSTEARATE 03A - Eyebrow Pencil 1GLYCERYL HYDROXYSTEARATE 03D - Eye Lotion 1GLYCERYL HYDROXYSTEARATE 03F - Mascara 1GLYCERYL HYDROXYSTEARATE 03G - Other Eye Makeup Preparati 7GLYCERYL HYDROXYSTEARATE 12F - Moisturizing 2GLYCERYL HYDROXYSTEARATE 12G - Night 1GLYCERYL HYDROXYSTEARATE 13A - Suntan Gels, Creams, and Li 1

GLYCERYL ISOSTEARATE 03C - Eye Shadow 4GLYCERYL ISOSTEARATE 05I - Other Hair Preparations 1GLYCERYL ISOSTEARATE 06A - Hair Dyes and Colors (all type 65GLYCERYL ISOSTEARATE 06B - Hair Tints 23GLYCERYL ISOSTEARATE 07C - Foundations 2


GLYCERYL ISOSTEARATE 07E - Lipstick 1GLYCERYL ISOSTEARATE 11E - Shaving Cream 1GLYCERYL ISOSTEARATE 12A - Cleansing 1GLYCERYL ISOSTEARATE 12F - Moisturizing 5GLYCERYL ISOSTEARATE 12J - Other Skin Care Preps 1

GLYCERYL ISOTRIDECANOATE/STEARATE/ADIPATE 12F - Moisturizing 1

GLYCERYL LANOLATE 12F - Moisturizing 1

GLYCERYL LAURATE 01B - Baby Lotions, Oils, Powders, 3GLYCERYL LAURATE 01C - Other Baby Products 3GLYCERYL LAURATE 02D - Other Bath Preparations 3GLYCERYL LAURATE 03B - Eyeliner 1GLYCERYL LAURATE 03C - Eye Shadow 2GLYCERYL LAURATE 03D - Eye Lotion 1GLYCERYL LAURATE 03E - Eye Makeup Remover 1GLYCERYL LAURATE 03G - Other Eye Makeup Preparati 4GLYCERYL LAURATE 04E - Other Fragrance Preparation 1GLYCERYL LAURATE 05A - Hair Conditioner 2GLYCERYL LAURATE 05F - Shampoos (non-coloring) 17GLYCERYL LAURATE 05G - Tonics, Dressings, and Othe 2GLYCERYL LAURATE 05I - Other Hair Preparations 5GLYCERYL LAURATE 07A - Blushers (all types) 2GLYCERYL LAURATE 07B - Face Powders 1GLYCERYL LAURATE 07C - Foundations 4GLYCERYL LAURATE 07E - Lipstick 6GLYCERYL LAURATE 07I - Other Makeup Preparations 3GLYCERYL LAURATE 09C - Other Oral Hygiene Products 2GLYCERYL LAURATE 10A - Bath Soaps and Detergents 38GLYCERYL LAURATE 10B - Deodorants (underarm) 15GLYCERYL LAURATE 10E - Other Personal Cleanliness P 23GLYCERYL LAURATE 11A - Aftershave Lotion 3GLYCERYL LAURATE 11E - Shaving Cream 4GLYCERYL LAURATE 11G - Other Shaving Preparation P 2GLYCERYL LAURATE 12A - Cleansing 16GLYCERYL LAURATE 12C - Face and Neck (exc shave) 3GLYCERYL LAURATE 12D - Body and Hand (exc shave) 7GLYCERYL LAURATE 12F - Moisturizing 18GLYCERYL LAURATE 12G - Night 2GLYCERYL LAURATE 12H - Paste Masks (mud packs) 1GLYCERYL LAURATE 12J - Other Skin Care Preps 13GLYCERYL LAURATE 13B - Indoor Tanning Preparations 2

GLYCERYL LINOLEATE 01B - Baby Lotions, Oils, Powders, 2GLYCERYL LINOLEATE 03D - Eye Lotion 2GLYCERYL LINOLEATE 03E - Eye Makeup Remover 1GLYCERYL LINOLEATE 03G - Other Eye Makeup Preparati 5GLYCERYL LINOLEATE 05A - Hair Conditioner 5GLYCERYL LINOLEATE 05B - Hair Spray (aerosol fixatives) 1GLYCERYL LINOLEATE 05F - Shampoos (non-coloring) 5GLYCERYL LINOLEATE 05G - Tonics, Dressings, and Othe 1GLYCERYL LINOLEATE 05I - Other Hair Preparations 5GLYCERYL LINOLEATE 06D - Hair Shampoos (coloring) 1GLYCERYL LINOLEATE 07E - Lipstick 1


GLYCERYL LINOLEATE 08B - Cuticle Softeners 1GLYCERYL LINOLEATE 08E - Nail Polish and Enamel 1GLYCERYL LINOLEATE 08G - Other Manicuring Preparation 2GLYCERYL LINOLEATE 10A - Bath Soaps and Detergents 1GLYCERYL LINOLEATE 12A - Cleansing 1GLYCERYL LINOLEATE 12C - Face and Neck (exc shave) 25GLYCERYL LINOLEATE 12D - Body and Hand (exc shave) 5GLYCERYL LINOLEATE 12F - Moisturizing 8GLYCERYL LINOLEATE 12G - Night 7GLYCERYL LINOLEATE 12H - Paste Masks (mud packs) 3GLYCERYL LINOLEATE 12J - Other Skin Care Preps 4

GLYCERYL LINOLENATE 01B - Baby Lotions, Oils, Powders, 2GLYCERYL LINOLENATE 03D - Eye Lotion 2GLYCERYL LINOLENATE 03E - Eye Makeup Remover 1GLYCERYL LINOLENATE 03G - Other Eye Makeup Preparati 4GLYCERYL LINOLENATE 05A - Hair Conditioner 5GLYCERYL LINOLENATE 05B - Hair Spray (aerosol fixatives) 1GLYCERYL LINOLENATE 05F - Shampoos (non-coloring) 5GLYCERYL LINOLENATE 05G - Tonics, Dressings, and Othe 1GLYCERYL LINOLENATE 05I - Other Hair Preparations 5GLYCERYL LINOLENATE 06D - Hair Shampoos (coloring) 1GLYCERYL LINOLENATE 07E - Lipstick 1GLYCERYL LINOLENATE 08B - Cuticle Softeners 1GLYCERYL LINOLENATE 08E - Nail Polish and Enamel 1GLYCERYL LINOLENATE 08G - Other Manicuring Preparation 2GLYCERYL LINOLENATE 10A - Bath Soaps and Detergents 1GLYCERYL LINOLENATE 12A - Cleansing 2GLYCERYL LINOLENATE 12C - Face and Neck (exc shave) 14GLYCERYL LINOLENATE 12D - Body and Hand (exc shave) 6GLYCERYL LINOLENATE 12F - Moisturizing 7GLYCERYL LINOLENATE 12G - Night 4GLYCERYL LINOLENATE 12J - Other Skin Care Preps 4

GLYCERYL OLEATE 01A - Baby Shampoos 5GLYCERYL OLEATE 01B - Baby Lotions, Oils, Powders, 2GLYCERYL OLEATE 01C - Other Baby Products 6GLYCERYL OLEATE 02A - Bath Oils, Tablets, and Salts 2GLYCERYL OLEATE 02B - Bubble Baths 17GLYCERYL OLEATE 02D - Other Bath Preparations 2GLYCERYL OLEATE 03A - Eyebrow Pencil 9GLYCERYL OLEATE 03B - Eyeliner 16GLYCERYL OLEATE 03C - Eye Shadow 36GLYCERYL OLEATE 03D - Eye Lotion 3GLYCERYL OLEATE 03E - Eye Makeup Remover 1GLYCERYL OLEATE 03F - Mascara 10GLYCERYL OLEATE 03G - Other Eye Makeup Preparati 12GLYCERYL OLEATE 04E - Other Fragrance Preparation 1GLYCERYL OLEATE 05A - Hair Conditioner 17GLYCERYL OLEATE 05B - Hair Spray (aerosol fixatives) 1GLYCERYL OLEATE 05F - Shampoos (non-coloring) 83GLYCERYL OLEATE 05G - Tonics, Dressings, and Othe 2GLYCERYL OLEATE 05I - Other Hair Preparations 10GLYCERYL OLEATE 06A - Hair Dyes and Colors (all type 1GLYCERYL OLEATE 06D - Hair Shampoos (coloring) 2GLYCERYL OLEATE 06G - Hair Bleaches 2GLYCERYL OLEATE 07A - Blushers (all types) 1


GLYCERYL OLEATE 07B - Face Powders 7GLYCERYL OLEATE 07C - Foundations 4GLYCERYL OLEATE 07E - Lipstick 29GLYCERYL OLEATE 07F - Makeup Bases 2GLYCERYL OLEATE 07H - Makeup Fixatives 1GLYCERYL OLEATE 07I - Other Makeup Preparations 10GLYCERYL OLEATE 09B - Mouthwashes and Breath Fre 5GLYCERYL OLEATE 10A - Bath Soaps and Detergents 154GLYCERYL OLEATE 10C - Douches 3GLYCERYL OLEATE 10E - Other Personal Cleanliness P 50GLYCERYL OLEATE 11D - Preshave Lotions (all types) 1GLYCERYL OLEATE 11E - Shaving Cream 10GLYCERYL OLEATE 11G - Other Shaving Preparation P 25GLYCERYL OLEATE 12A - Cleansing 52GLYCERYL OLEATE 12C - Face and Neck (exc shave) 14GLYCERYL OLEATE 12D - Body and Hand (exc shave) 7GLYCERYL OLEATE 12E - Foot Powders and Sprays 1GLYCERYL OLEATE 12F - Moisturizing 29GLYCERYL OLEATE 12G - Night 6GLYCERYL OLEATE 12I - Skin Fresheners 1GLYCERYL OLEATE 12J - Other Skin Care Preps 6GLYCERYL OLEATE 13A - Suntan Gels, Creams, and Li 1GLYCERYL OLEATE 13B - Indoor Tanning Preparations 2GLYCERYL OLEATE 13C - Other Suntan Preparations 2

GLYCERYL OLEATE/ELAIDATE 05F - Shampoos (non-coloring) 2GLYCERYL OLEATE/ELAIDATE 12F - Moisturizing 2

GLYCERYL MONOPALMITATE 12A - Cleansing 1GLYCERYL MONOPALMITATE 12D - Body and Hand (exc shave) 3

GLYCERYL RICINOLEATE 03B - Eyeliner 10GLYCERYL RICINOLEATE 07C - Foundations 3GLYCERYL RICINOLEATE 07E - Lipstick 16GLYCERYL RICINOLEATE 07I - Other Makeup Preparations 3GLYCERYL RICINOLEATE 10A - Bath Soaps and Detergents 2GLYCERYL RICINOLEATE 11A - Aftershave Lotion 1GLYCERYL RICINOLEATE 12F - Moisturizing 6RICINOLEIN 03A - Eyebrow Pencil 1

GLYCERYL ROSINATE 03C - Eye Shadow 2GLYCERYL ROSINATE 03F - Mascara 4GLYCERYL ROSINATE 05I - Other Hair Preparations 1GLYCERYL ROSINATE 06H - Other Hair Coloring Preparat 2GLYCERYL ROSINATE 07B - Face Powders 1GLYCERYL ROSINATE 07C - Foundations 5GLYCERYL ROSINATE 07E - Lipstick 20GLYCERYL ROSINATE 07I - Other Makeup Preparations 1GLYCERYL ROSINATE 12B - Depilatories 12GLYCERYL ROSINATE 12F - Moisturizing 2

GLYCERYL STEARATE 01A - Baby Shampoos 1GLYCERYL STEARATE 01B - Baby Lotions, Oils, Powders, 28GLYCERYL STEARATE 01C - Other Baby Products 4


GLYCERYL STEARATE 02A - Bath Oils, Tablets, and Salts 1GLYCERYL STEARATE 02B - Bubble Baths 6GLYCERYL STEARATE 02D - Other Bath Preparations 3GLYCERYL STEARATE 03A - Eyebrow Pencil 14GLYCERYL STEARATE 03B - Eyeliner 49GLYCERYL STEARATE 03C - Eye Shadow 53GLYCERYL STEARATE 03D - Eye Lotion 115GLYCERYL STEARATE 03E - Eye Makeup Remover 9GLYCERYL STEARATE 03F - Mascara 247GLYCERYL STEARATE 03G - Other Eye Makeup Preparati 79GLYCERYL STEARATE 04B - Perfumes 8GLYCERYL STEARATE 04E - Other Fragrance Preparation 9GLYCERYL STEARATE 05A - Hair Conditioner 156GLYCERYL STEARATE 05C - Hair Straighteners 2GLYCERYL STEARATE 05D - Permanent Waves 5GLYCERYL STEARATE 05E - Rinses (non-coloring) 9GLYCERYL STEARATE 05F - Shampoos (non-coloring) 25GLYCERYL STEARATE 05G - Tonics, Dressings, and Othe 79GLYCERYL STEARATE 05I - Other Hair Preparations 41GLYCERYL STEARATE 06A - Hair Dyes and Colors (all type 151GLYCERYL STEARATE 06B - Hair Tints 21GLYCERYL STEARATE 06C - Hair Rinses (coloring) 6GLYCERYL STEARATE 06D - Hair Shampoos (coloring) 1GLYCERYL STEARATE 06F - Hair Lighteners with Color 1GLYCERYL STEARATE 06H - Other Hair Coloring Preparat 20GLYCERYL STEARATE 07A - Blushers (all types) 3GLYCERYL STEARATE 07B - Face Powders 20GLYCERYL STEARATE 07C - Foundations 41GLYCERYL STEARATE 07D - Leg and Body Paints 14GLYCERYL STEARATE 07E - Lipstick 30GLYCERYL STEARATE 07F - Makeup Bases 23GLYCERYL STEARATE 07I - Other Makeup Preparations 38GLYCERYL STEARATE 08B - Cuticle Softeners 4GLYCERYL STEARATE 08C - Nail Creams and Lotions 4GLYCERYL STEARATE 08F - Nail Polish and Enamel Remo 1GLYCERYL STEARATE 08G - Other Manicuring Preparation 2GLYCERYL STEARATE 10A - Bath Soaps and Detergents 54GLYCERYL STEARATE 10B - Deodorants (underarm) 42GLYCERYL STEARATE 10C - Douches 1GLYCERYL STEARATE 10E - Other Personal Cleanliness P 87GLYCERYL STEARATE 11A - Aftershave Lotion 51GLYCERYL STEARATE 11E - Shaving Cream 23GLYCERYL STEARATE 11G - Other Shaving Preparation P 5GLYCERYL STEARATE 12A - Cleansing 229GLYCERYL STEARATE 12B - Depilatories 1GLYCERYL STEARATE 12C - Face and Neck (exc shave) 495GLYCERYL STEARATE 12D - Body and Hand (exc shave) 877GLYCERYL STEARATE 12E - Foot Powders and Sprays 8GLYCERYL STEARATE 12F - Moisturizing 1297GLYCERYL STEARATE 12G - Night 205GLYCERYL STEARATE 12H - Paste Masks (mud packs) 106GLYCERYL STEARATE 12I - Skin Fresheners 5GLYCERYL STEARATE 12J - Other Skin Care Preps 225GLYCERYL STEARATE 13A - Suntan Gels, Creams, and Li 25GLYCERYL STEARATE 13B - Indoor Tanning Preparations 80GLYCERYL STEARATE 13C - Other Suntan Preparations 14

GLYCERYL STEARATE SE 01B - Baby Lotions, Oils, Powders, 3


GLYCERYL STEARATE SE 03B - Eyeliner 1GLYCERYL STEARATE SE 03C - Eye Shadow 15GLYCERYL STEARATE SE 03D - Eye Lotion 10GLYCERYL STEARATE SE 03E - Eye Makeup Remover 1GLYCERYL STEARATE SE 03F - Mascara 20GLYCERYL STEARATE SE 03G - Other Eye Makeup Preparati 12GLYCERYL STEARATE SE 04E - Other Fragrance Preparation 1GLYCERYL STEARATE SE 05A - Hair Conditioner 22GLYCERYL STEARATE SE 05F - Shampoos (non-coloring) 4GLYCERYL STEARATE SE 05G - Tonics, Dressings, and Othe 14GLYCERYL STEARATE SE 05I - Other Hair Preparations 5GLYCERYL STEARATE SE 06A - Hair Dyes and Colors (all type 317GLYCERYL STEARATE SE 06B - Hair Tints 22GLYCERYL STEARATE SE 06H - Other Hair Coloring Preparat 1GLYCERYL STEARATE SE 07A - Blushers (all types) 2GLYCERYL STEARATE SE 07C - Foundations 9GLYCERYL STEARATE SE 07E - Lipstick 1GLYCERYL STEARATE SE 07F - Makeup Bases 2GLYCERYL STEARATE SE 07I - Other Makeup Preparations 3GLYCERYL STEARATE SE 08C - Nail Creams and Lotions 1GLYCERYL STEARATE SE 10A - Bath Soaps and Detergents 8GLYCERYL STEARATE SE 10B - Deodorants (underarm) 1GLYCERYL STEARATE SE 10E - Other Personal Cleanliness P 13GLYCERYL STEARATE SE 11A - Aftershave Lotion 5GLYCERYL STEARATE SE 11E - Shaving Cream 5GLYCERYL STEARATE SE 12A - Cleansing 61GLYCERYL STEARATE SE 12B - Depilatories 7GLYCERYL STEARATE SE 12C - Face and Neck (exc shave) 67GLYCERYL STEARATE SE 12D - Body and Hand (exc shave) 185GLYCERYL STEARATE SE 12E - Foot Powders and Sprays 1GLYCERYL STEARATE SE 12F - Moisturizing 500GLYCERYL STEARATE SE 12G - Night 29GLYCERYL STEARATE SE 12H - Paste Masks (mud packs) 15GLYCERYL STEARATE SE 12I - Skin Fresheners 3GLYCERYL STEARATE SE 12J - Other Skin Care Preps 35GLYCERYL STEARATE SE 13A - Suntan Gels, Creams, and Li 7GLYCERYL STEARATE SE 13B - Indoor Tanning Preparations 12

GLYCERYL UNDECYLENATE 03D - Eye Lotion 1GLYCERYL UNDECYLENATE 03F - Mascara 1GLYCERYL UNDECYLENATE 05A - Hair Conditioner 1GLYCERYL UNDECYLENATE 05G - Tonics, Dressings, and Othe 1GLYCERYL UNDECYLENATE 12C - Face and Neck (exc shave) 3GLYCERYL UNDECYLENATE 12D - Body and Hand (exc shave) 2GLYCERYL UNDECYLENATE 12E - Foot Powders and Sprays 1GLYCERYL UNDECYLENATE 12F - Moisturizing 5GLYCERYL UNDECYLENATE 12G - Night 1GLYCERYL UNDECYLENATE 12H - Paste Masks (mud packs) 1


Concentration of Use by FDA Product Category – Glyceryl Monoesters*

Glyceryl Abietate Glyceryl Abietate/Maleate Glyceryl Acetate Glyceryl Adipate Glyceryl Alginate Glyceryl Arachidate Glyceryl Arachidonate Glyceryl Behenate Glyceryl Behenate/Eicosadioate Glyceryl Caprate Glyceryl Caprylate Glyceryl Caprylate/Caprate Glyceryl Citrate/Lactate/Linoleate/Oleate Glyceryl Cocoate Glyceryl Cocoate/Citrate/Lactate Glyceryl Collagenate Glyceryl Erucate Glyceryl Ethylhexanoate Glyceryl Ethylhexanoate/Stearate/Adipate Glyceryl Glycyrrhetinate Glyceryl Heptanoate Glyceryl Hydrogenated Rapeseedate Glyceryl Hydrogenated Rosinate Glyceryl Hydrogenated Soyate Glyceryl Hydroxystearate Glyceryl Hydroxystearate/Oleate Esters Glyceryl Isopalmitate Glyceryl Isostearate Glyceryl Isostearate/Myristate Glyceryl Isotridecanoate/Stearate/Adipate Glyceryl Lanolate

Glyceryl Laurate Glyceryl Laurate/Oleate Glyceryl Laurate SE Glyceryl Linoleate Glyceryl Linolenate Glyceryl Montanate Glyceryl Myristate Glyceryl Oleate Glyceryl Oleate/Elaidate Glyceryl Oleate SE Glyceryl Olivate Glyceryl Palmitate Glyceryl Palmitate/Stearate Glyceryl Palmitoleate Glyceryl Pentadecanoate Glyceryl Polyacrylate Glyceryl/Polyglyceryl-6 Isostearate/Behenate Esters Glyceryl Polyisobutenylsuccinate Glyceryl Polymethacrylate Glyceryl Ricinoleate Glyceryl Ricinoleate SE Glyceryl Rosinate Glyceryl/Sorbitol Oleate/Hydroxystearate Glyceryl Stearate/Malate Glyceryl Tallowate Glyceryl Thioglycolate Glyceryl Thiopropionate Glyceryl Undecylenate Glyceryl Stearate Glyceryl Stearate SE

Ingredient Product Category Maximum Concentration of Use Glyceryl Behenate Eyeliner 0.3% Glyceryl Behenate Eye shadow 0.38% Glyceryl Behenate Mascara 1.5% Glyceryl Behenate Tonics, dressings and other hair

grooming aids 0.48%

Glyceryl Behenate Foundations 0.31-2.5% Glyceryl Behenate Makeup bases 0.43% Glyceryl Behenate Other manicuring preparations 0.27% (rinse-off) Glyceryl Behenate Face and neck products

not spray 0.45%

Glyceryl Behenate Body and hand products not spray

2%


Glyceryl Behenate/Eicosadioate Eyebrow pencil 3.4% Glyceryl Behenate/Eicosadioate Eyeliner 0.11% Glyceryl Behenate/Eicosadioate Rinses (noncoloring) 0.4% Glyceryl Behenate/Eicosadioate Tonics, dressings and other hair

grooming aids 0.03%

Glyceryl Behenate/Eicosadioate Lipstick 0.75-3% Glyceryl Behenate/Eicosadioate Other personal cleanliness

products 4.1%

Glyceryl Behenate/Eicosadioate Skin cleansing products 4% Glyceryl Behenate/Eicosadioate Face and neck products

not spray 1.5%

Glyceryl Behenate/Eicosadioate Body and hand products not spray

0.8%

Glyceryl Caprate Deodorants pump spray

1%

Glyceryl Caprylate Eyebrow pencil 1% Glyceryl Caprylate Eye liner 1% Glyceryl Caprylate Eye shadow 0.28-1% Glyceryl Caprylate Mascara 0.03-0.06% Glyceryl Caprylate Other eye makeup preparations 1% Glyceryl Caprylate Hair conditioners 1% Glyceryl Caprylate Shampoos (noncoloring) 0.01-1% Glyceryl Caprylate Tonics, dressings and other hair

grooming aids 1%

Glyceryl Caprylate Blushers (all types) 1.5% Glyceryl Caprylate Face powders 0.98% Glyceryl Caprylate Foundations 1% Glyceryl Caprylate Lipstick 0.3-1% Glyceryl Caprylate Rouges 0.5% Glyceryl Caprylate Deodorants

not spray 1.5%

Glyceryl Caprylate Beard softeners 1% Glyceryl Caprylate Skin cleansing products 0.05-1.5% Glyceryl Caprylate Face and neck products

not spray 0.001-1%

Glyceryl Caprylate Body and hand products not spray

1%

Glyceryl Caprylate Other skin care preparations 0.05% (leave-on) Glyceryl Caprylate Suntan products

not spray 0.15%


Hair conditioners 0.004%


Hair sprays pump spray

0.0004%


Rinses (noncoloring) 0.004%


Glyceryl Cocoate Shampoos (noncoloring) 1% Glyceryl Cocoate Bath soaps and detergents 2% Glyceryl Cocoate Deodorant

pump spray 2%

Glyceryl Cocoate Aftershave lotions 2% Glyceryl Ethylhexanoate/Stearate/Adipate

Eyeliner 3%

Glyceryl Ethylhexanoate/Stearate/Adipate

Eye shadow 0.8-1.2%


Blushers 0.8%


Face powders 1-1.4%


Foundations 0.6-2%

Glyceryl Hydrogenated Rosinate Mascara 3-4.8% Glyceryl Hydrogenated Rosinate Tonics, dressings and other hair

grooming aids 6.5%

Glyceryl Hydrogenated Rosinate Lipstick 4-10% Glyceryl Hydrogenated Rosinate Depilatories 65-76-8% Glyceryl Hydroxystearate Eyebrow pencil 1% Glyceryl Hydroxystearate Mascara 2% Glyceryl Hydroxystearate Deodorants

not spray 0.9%

Glyceryl Hydroxystearate Body and hand products not spray

0.5%

Glyceryl Hydroxystearate Moisturizing products not spray

0.74%

Glyceryl Isostearate Hair conditioners 0.3% Glyceryl Isostearate Blushers 1% Glyceryl Isostearate Foundations 2% Glyceryl Isostearate Skin cleansing products 1.5% Glyceryl Isostearate Face and neck products

not spray 0.8-1%

Glyceryl Isostearate Suntan products not spray

1%

Glyceryl Isostearate/Myristate Face and neck products not spray

1%

Glyceryl Laurate Bubble baths 1% Glyceryl Laurate Eye lotion 0.48% Glyceryl Laurate Eye makeup removers 0.000065-0.24% Glyceryl Laurate Shampoos (noncoloring) 0.088-1.5% Glyceryl Laurate Tonics, dressings and other hair

grooming aids 0.2%

Glyceryl Laurate Bath soaps and detergents 0.3-4.5% Glyceryl Laurate Other personal cleanliness 0.000065%


products Glyceryl Laurate Skin cleansing products 0.1-0.24% Glyceryl Laurate Face and neck products

not spray 0.1%

Glyceryl Laurate Body and hand products not spray

0.5%

Glyceryl Laurate Moisturizing products not spray

0.000065%

Glyceryl Linoleate Eyeliner 2.5% Glyceryl Linoleate Tonics, dressings and other hair

grooming aids 0.000055%

Glyceryl Linoleate Foundations 0.003% Glyceryl Linoleate Lipstick 0.056-2.5% Glyceryl Linoleate Basecoats and undercoats 0.019% Glyceryl Linoleate Cuticle softeners 4.6% Glyceryl Linoleate Nail creams and lotions 4.6% Glyceryl Linoleate Face and neck products

not sprays 0.003-0.75%

Glyceryl Linoleate Skin fresheners 0.0002% Glyceryl Linoleate Other skin care preparations 0.11% Glyceryl Linolenate Eyeliner 0.2% Glyceryl Linolenate Tonics, dressings and other hair


Glyceryl Linolenate Lipstick 0.046-0.2% Glyceryl Linolenate Basecoats and undercoats 0.001% Glyceryl Linolenate Cuticle softeners 0.4% Glyceryl Linolenate Nail creams and lotions 0.4% Glyceryl Linolenate Other skin care preparations 0.09% Glyceryl Myristate Face and neck products

not spray 1%

Glyceryl Oleate Eyebrow pencil 0.01-0.06% Glyceryl Oleate Eyeliner 0.0075-0.062% Glyceryl Oleate Eye shadow 0.0075-0.75% Glyceryl Oleate Eye lotion 1% Glyceryl Oleate Mascara 0.0075-2.3% Glyceryl Oleate Colognes and toilet waters 1.4% Glyceryl Oleate Hair conditioners 0.5-2.7% Glyceryl Oleate Rinses (noncoloring) 0.3% Glyceryl Oleate Shampoo (noncoloring) 0.1-1.5% Glyceryl Oleate Tonics, dressings and other hair


Glyceryl Oleate Other hair preparations (noncoloring)

0.15%

Glyceryl Oleate Hair dyes and colors 2% Glyceryl Oleate Foundations 0.0075% Glyceryl Oleate Lipstick 0.0001-0.075%


Glyceryl Oleate Makeup bases 2% Glyceryl Oleate Cuticle softeners 0.015% Glyceryl Oleate Bath soaps and detergents 0.25-2.4% Glyceryl Oleate Other personal cleanliness

products 0.3-2%

Glyceryl Oleate Aftershave lotions 0.3% Glyceryl Oleate Shaving cream 2% Glyceryl Oleate Skin cleansing 0.11-1% Glyceryl Oleate Face and neck products

not spray 0.3-1.8%

Glyceryl Oleate Body and hand products not spray

0.0028-3%

Glyceryl Oleate Moisturizing products not spray

0.0083%

Glyceryl Oleate Night products not spray

0.0083-0.45%

Glyceryl Oleate Skin fresheners 0.13% Glyceryl Oleate Other skin care preparations 0.26% (rinse-off) Glyceryl Oleate Suntan products

not spray 0.075%

Glyceryl Polyacrylate Eye lotion 0.03-0.3% Glyceryl Polyacrylate Mascara 5.3% Glyceryl Polyacrylate Hair sprays

pump spray 0.35%

Glyceryl Polyacrylate Tonics, dressings and other hair grooming aids

0.2%

Glyceryl Polyacrylate Aftershave lotions 0.17% Glyceryl Polyacrylate Skin cleansing products 0.68% Glyceryl Polyacrylate Face and neck products

not spray 0.1-1.2%

Glyceryl Polyacrylate Body and hand products not spray

0.029-0.87%

Glyceryl Polyacrylate Foot products 0.025% Glyceryl Polyacrylate Moisturizing products

not spray 0.34%

Glyceryl Polyacrylate Suntan products not spray

0.15%

Glyceryl Polyacrylate Other suntan preparations 0.011% Glyceryl/Polyglyceryl-6 Isostearate/Behenate Esters

Body and hand products not spray

2%

Glyceryl Polymethacrylate Eyebrow pencil 32.8% Glyceryl Polymethacrylate Eye shadow 0.08% Glyceryl Polymethacrylate Eye lotion 0.8% Glyceryl Polymethacrylate Mascara 11.3% Glyceryl Polymethacrylate Other eye makeup preparations 0.024% Glyceryl Polymethacrylate Hair sprays


aerosol 0.091% Glyceryl Polymethacrylate Foundations 0.055-0.8% Glyceryl Polymethacrylate Makeup bases 0.047% Glyceryl Polymethacrylate Aftershave lotions 0.16% Glyceryl Polymethacrylate Shaving soap 0.26% Glyceryl Polymethacrylate Skin cleansing 7.7% Glyceryl Polymethacrylate Face and neck products

not spray 0.46-7.9%

Glyceryl Polymethacrylate Body and hand products not spray

3.4-3.6%

Glyceryl Polymethacrylate Foot products 0.18% Glyceryl Polymethacrylate Other skin care preparations 0.23% (leave-on) Glyceryl Polymethacrylate Suntan products

not spray 0.9%

Glyceryl Ricinoleate Eyeliner 1.5-11.6% Glyceryl Ricinoleate Eye shadow 5-11.1% Glyceryl Ricinoleate Foundations 10.5% Glyceryl Ricinoleate Lipstick 11.9-15.2% Glyceryl Ricinoleate Makeup bases 12.6% Glyceryl Ricinoleate SE Eyebrow pencil 6.8% Glyceryl Rosinate Eyeliner 6% Glyceryl Rosinate Eye shadow 0.3-4% Glyceryl Rosinate Mascara 8% Glyceryl Rosinate Other hair coloring preparations 2.6% (rinse-off) Glyceryl Rosinate Blushers 0.018% Glyceryl Rosinate Foundations 4.1% Glyceryl Rosinate Lipstick 0.48-0.5% Glyceryl Rosinate Other makeup preparations 0.14% Glyceryl Rosinate Depilatories 72-96% Glyceryl Stearate/Malate Eyebrow pencil 0.25% Glyceryl Stearate/Malate Mascara 0.25% Glyceryl Thioglycolate Permanent waves 17.2-80% Glyceryl Undecylanate Moisturizing products

not spray 1%

Glyceryl Undecylanate Paste masks and mud packs 1% Glyceryl Stearate Baby lotions, oils and creams

not powders 1.8%

Glyceryl Stearate Other baby products 1.8% Glyceryl Stearate Bubble baths 1% Glyceryl Stearate Other bath preparations 10% Glyceryl Stearate Eyebrow pencil 0.014-2.5% Glyceryl Stearate Eye liner 0.069-2.2% Glyceryl Stearate Eye shadow 0.018-3% Glyceryl Stearate Eye lotion 1.5-4.8% Glyceryl Stearate Eye makeup remover 0.5-1.3% Glyceryl Stearate Mascara 2.6-9%


Glyceryl Stearate Other eye makeup preparations 2.7-2.8% Glyceryl Stearate Perfumes 2-14% Glyceryl Stearate Sachets 14% Glyceryl Stearate Other fragrance preparations 2-12.6% Glyceryl Stearate Hair conditioners 0.15-4.8% Glyceryl Stearate Hair straighteners 0.88-1.8% Glyceryl Stearate Rinses (noncoloring) 0.75-0.85% Glyceryl Stearate Shampoos (noncoloring) 0.5-2% Glyceryl Stearate Tonics, dressings and other hair

grooming aids 0.5-4.1%

Glyceryl Stearate Other hair preparations (noncoloring)

4%

Glyceryl Stearate Hair dyes and colors 0.9-7% Glyceryl Stearate Hair bleaches 2.2% Glyceryl Stearate Other hair coloring preparations 2% Glyceryl Stearate Blushers 2.5% Glyceryl Stearate Face powders 0.05-3% Glyceryl Stearate Foundations 2-7.1% Glyceryl Stearate Lipstick 0.0002-3% Glyceryl Stearate Makeup bases 0.075-2% Glyceryl Stearate Makeup fixatives 1.2% Glyceryl Stearate Other makeup preparations 0.88-2% Glyceryl Stearate Cuticle softeners 1.4-3% Glyceryl Stearate Nail creams and lotions 2-6% Glyceryl Stearate Nail polish and enamel removers 0.006% Glyceryl Stearate Other manicuring preparations 2-5% Glyceryl Stearate Bath soaps and detergents 1.1-1.3% Glyceryl Stearate Deodorants

not spray 0.25-17%

Glyceryl Stearate Other personal cleanliness products

0.78-18% (rinse-off)

Glyceryl Stearate Aftershave lotions 0.5-2.1% Glyceryl Stearate Shaving cream 0.05% Glyceryl Stearate Other shaving preparations 2% (leave-on) Glyceryl Stearate Skin cleansing 0.25-18.9% Glyceryl Stearate Face and neck products

not spray 0.75-5%

Glyceryl Stearate Body and hand products not spray

0.0083-10%

Glyceryl Stearate Foot products 2.3-6% Glyceryl Stearate Moisturizing products

not spray 0.0083-5%

Glyceryl Stearate Night products not spray

0.0083-3.6%

Glyceryl Stearate Paste masks and mud packs 0.5-11% Glyceryl Stearate Other skin preparations 1.1-6%


Glyceryl Stearate Suntan products not spray

1.3-3%

Glyceryl Stearate Indoor tanning preparations 1-4.8% Glyceryl Stearate Other suntan preparations 1.2-2% Glyceryl Stearate SE Other bath preparations 6% Glyceryl Stearate SE Eye liner 1.7% Glyceryl Stearate SE Eye lotion 0.2-3% Glyceryl Stearate SE Mascara 0.47-5% Glyceryl Stearate SE Other eye makeup preparations 5% Glyceryl Stearate SE Other fragrance preparations 3% Glyceryl Stearate SE Hair conditioners 0.5-4% Glyceryl Stearate SE Rinses (noncoloring) 1-1.2% Glyceryl Stearate SE Shampoos (noncoloring) 3.6% Glyceryl Stearate SE Tonics, dressings and other hair

grooming aids 0.001-3%

Glyceryl Stearate SE Hair dyes and colors 3-6% Glyceryl Stearate SE Hair bleaches 6% Glyceryl Stearate SE Foundations 0.5-5.7% Glyceryl Stearate SE Makeup bases 2-2.2% Glyceryl Stearate SE Other makeup preparations 2.2-3.3% Glyceryl Stearate SE Bath soaps and detergents 5% Glyceryl Stearate SE Other personal cleanliness

products 3-5% (5% in a foot scrub)

Glyceryl Stearate SE Aftershave lotions 0.5-3% Glyceryl Stearate SE Skin cleansing products 1-6% Glyceryl Stearate SE Depilatories 3% Glyceryl Stearate SE Face and neck products

not spray 0.2-10%

Glyceryl Stearate SE Body and hand products not spray

0.4-10%

Glyceryl Stearate SE Foot products 2-3.9% Glyceryl Stearate SE Moisturizing products

not spray 0.3-4.8%

Glyceryl Stearate SE Night products not spray

0.75-5%

Glyceryl Stearate SE Paste masks and mud packs 4% Glyceryl Stearate SE Other skin care preparations 3-10% Glyceryl Stearate SE Suntan products

not spray 0.3-0.95%

Glyceryl Stearate SE Indoor tanning preparations 1.5-2.9% *Ingredients included in the title of the table, but not found in the table were included in the concentration of use survey, but no uses were reported.

Information collected in 2014 Table prepared April 28, 2014

Updated August 7, 2015: Glyceryl Rosinate, mascara corrected from 99.9% to 8%


Download Amended Safety Assessment of Monoglyceryl ...

Documents

Transcript of Download Amended Safety Assessment of Monoglyceryl ...